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Montalbetti N, Manrique-Maldonado G, Ikeda Y, Dalghi M, Kanai A, Apodaca G, Carattino MD. Expression of Acid-Sensing Ion Channel 3 in Afferents Averts Long-Term Sensitization and the Development of Visceral Pain. Int J Mol Sci 2024; 25:12503. [PMID: 39684215 DOI: 10.3390/ijms252312503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/07/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024] Open
Abstract
Sensitization of primary afferents is essential for the development of pain, but the molecular events involved in this process and its reversal are poorly defined. Recent studies revealed that acid-sensing ion channels (ASICs) control the excitability of nociceptors in the urinary bladder. Using genetic and pharmacological tools we show that ASICs are functionally coupled with voltage-gated Ca2+ channels to mediate Ca2+ transients evoked by acidification in sensory neurons. Genetic deletion of Asic3 of these sensory neurons does not alter the mechanical response of bladder afferents to distension in naïve mice. Both control and sensory neuron conditional Asic3 knockout (Asic3-KO) mice with chemical cystitis induced by cyclophosphamide (CYP) administration exhibit frequent low volume voiding events. However, these changes are transient and revert over time. Of major significance, in Asic3-KO mice, CYP treatment results in the sensitization of a subset of bladder afferents and pelvic allodynia that persist beyond the resolution of the inflammatory process. Thus, ASICs function is necessary to prevent long-term sensitization of visceral nociceptors.
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Affiliation(s)
- Nicolas Montalbetti
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburg, PA 15261, USA
| | | | - Youko Ikeda
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburg, PA 15261, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburg, PA 15261, USA
| | - Marianela Dalghi
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburg, PA 15261, USA
| | - Anthony Kanai
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburg, PA 15261, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburg, PA 15261, USA
| | - Gerard Apodaca
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburg, PA 15261, USA
- Department of Cell Biology, University of Pittsburgh, Pittsburg, PA 15261, USA
| | - Marcelo D Carattino
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburg, PA 15261, USA
- Department of Cell Biology, University of Pittsburgh, Pittsburg, PA 15261, USA
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Zhang Y, Dong D, Zhang J, Cheng K, Zhen F, Li M, Chen B. Pathology and physiology of acid-sensitive ion channels in the bladder. Heliyon 2024; 10:e38031. [PMID: 39347393 PMCID: PMC11437851 DOI: 10.1016/j.heliyon.2024.e38031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/08/2024] [Accepted: 09/16/2024] [Indexed: 10/01/2024] Open
Abstract
Acid-sensitive ion channels (ASICs) are sodium-permeable channels activated by extracellular acidification. They can be activated and trigger the inward flow of Na+ when the extracellular environment is acidic, leading to membrane depolarization and thus inducing action potentials in neurons. There are four ASIC genes in mammals (ASIC1-4). ASIC is widely expressed in humans. It is closely associated with pain, neurological disorders, multiple sclerosis, epilepsy, migraines, and many other disorders. Bladder pain syndrome/interstitial cystitis (BPS/IC) is a specific syndrome characterized by bladder pain. Recent studies have shown that ASICs are closely associated with the development of BPS/IC. A study revealed that ASIC levels are significantly elevated in a BPS/IC model. Additionally, researchers have reported differential changes in ASICs in the bladders of patients with neurogenic lower urinary tract dysfunction (NLUTD) caused by spinal cord injury (SCI). In this review, we summarize the structure and physiological functions of ASICs and focus on the mechanisms by which ASICs mediate bladder disease.
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Affiliation(s)
- Yang Zhang
- Department of Urology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Di Dong
- Department of Urology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jialong Zhang
- Department of Urology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Kang Cheng
- Department of Urology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Fang Zhen
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Mei Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Binghai Chen
- Department of Urology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Institute of Translational Medicine, Jiangsu University, China
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Wan X, Li F, Li Z, Zhou L. ASIC3-activated key enzymes of de novo lipid synthesis supports lactate-driven EMT and the metastasis of colorectal cancer cells. Cell Commun Signal 2024; 22:388. [PMID: 39095886 PMCID: PMC11295509 DOI: 10.1186/s12964-024-01762-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 07/22/2024] [Indexed: 08/04/2024] Open
Abstract
Acidic microenvironments is a cancer progression driver, unclear core mechanism hinders the discovery of new diagnostic or therapeutic targets. ASIC3 is an extracellular proton sensor and acid-sensitive, but its role in acidic tumor microenvironment of colorectal cancer is not reported. Functional analysis data show that colorectal cancer cells respond to specific concentration of lactate to accelerate invasion and metastasis, and ASIC3 is the main actor in this process. Mechanism reveal de novo lipid synthesis is a regulatory process of ASIC3, down-regulated ASIC3 increases and interacts with ACC1 and SCD1, which are key enzymes in de novo lipid synthesis pathway, this interaction results in increased unsaturated fatty acids, which in turn induce EMT to promote metastasis, and overexpression of ASIC3 reduces acidic TME-enhanced colorectal cancer metastasis. Clinical samples of colorectal cancer also exhibit decreased ASIC3 expression, and low ASIC3 expression is associated with metastasis and stage of colorectal cancer. This study is the first to identify the role of the ASIC3-ACC1/SCD1 axis in acid-enhanced colorectal cancer metastasis. The expression pattern of ASIC3 in colorectal cancer differs significantly from that in other types of cancers, ASIC3 may serve as a novel and reliable marker for acidic microenvironmental in colorectal cancer, and potentially a therapeutic target.
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Affiliation(s)
- Xing Wan
- Department of Pharmacology, Sichuan University West China School of Basic Medical Sciences & Forensic Medicine, Chengdu, 610041, China
- Department of Pharmacology, Hubei Minzu University Health Science Center, Enshi, 445000, China
| | - Feng Li
- Department of Pharmacology, Sichuan University West China School of Basic Medical Sciences & Forensic Medicine, Chengdu, 610041, China
| | - Zhigui Li
- Department of General Surgery, Colorectal Cancer Center, Sichuan University West China Hospital, Chengdu, 610041, China
| | - Liming Zhou
- Department of Pharmacology, Sichuan University West China School of Basic Medical Sciences & Forensic Medicine, Chengdu, 610041, China.
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Sun H, Yang T, Simon R, Xiong ZG, Leng T. Cholestane-3β,5α,6β-Triol Inhibits Acid-Sensing Ion Channels and Reduces Acidosis-Mediated Ischemic Brain Injury. Stroke 2024; 55:1660-1671. [PMID: 38660789 PMCID: PMC11126354 DOI: 10.1161/strokeaha.124.046963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 03/25/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND Activation of the acid-sensing ion channels (ASICs) by tissue acidosis, a common feature of brain ischemia, contributes to ischemic brain injury, while blockade of ASICs results in protection. Cholestane-3β,5α,6β-triol (Triol), a major cholesterol metabolite, has been demonstrated as an endogenous neuroprotectant; however, the mechanism underlying its neuroprotective activity remains elusive. In this study, we tested the hypothesis that inhibition of ASICs is a potential mechanism. METHODS The whole-cell patch-clamp technique was used to examine the effect of Triol on ASICs heterogeneously expressed in Chinese hamster ovary cells and ASICs endogenously expressed in primary cultured mouse cortical neurons. Acid-induced injury of cultured mouse cortical neurons and middle cerebral artery occlusion-induced ischemic brain injury in wild-type and ASIC1 and ASIC2 knockout mice were studied to examine the protective effect of Triol. RESULTS Triol inhibits ASICs in a subunit-dependent manner. In Chinese hamster ovary cells, it inhibits homomeric ASIC1a and ASIC3 without affecting ASIC1β and ASIC2a. In cultured mouse cortical neurons, it inhibits homomeric ASIC1a and heteromeric ASIC1a-containing channels. The inhibition is use-dependent but voltage- and pH-independent. Structure-activity relationship analysis suggests that hydroxyls at the 5 and 6 positions of the A/B ring are critical functional groups. Triol alleviates acidosis-mediated injury of cultured mouse cortical neurons and protects against middle cerebral artery occlusion-induced brain injury in an ASIC1a-dependent manner. CONCLUSIONS Our study identifies Triol as a novel ASIC inhibitor, which may serve as a new pharmacological tool for studying ASICs and may also be developed as a potential drug for treating stroke.
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Affiliation(s)
- Huawei Sun
- Department of Neurobiology, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA 30329, USA
| | - Tao Yang
- Department of Neurobiology, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA 30329, USA
| | - Roger Simon
- Department of Neurobiology, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA 30329, USA
| | - Zhi-gang Xiong
- Department of Neurobiology, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA 30329, USA
| | - Tiandong Leng
- Department of Neurobiology, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA 30329, USA
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Gründer S, Vanek J, Pissas KP. Acid-sensing ion channels and downstream signalling in cancer cells: is there a mechanistic link? Pflugers Arch 2024; 476:659-672. [PMID: 38175291 PMCID: PMC11006730 DOI: 10.1007/s00424-023-02902-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/05/2024]
Abstract
It is increasingly appreciated that the acidic microenvironment of a tumour contributes to its evolution and clinical outcomes. However, our understanding of the mechanisms by which tumour cells detect acidosis and the signalling cascades that it induces is still limited. Acid-sensing ion channels (ASICs) are sensitive receptors for protons; therefore, they are also candidates for proton sensors in tumour cells. Although in non-transformed tissue, their expression is mainly restricted to neurons, an increasing number of studies have reported ectopic expression of ASICs not only in brain cancer but also in different carcinomas, such as breast and pancreatic cancer. However, because ASICs are best known as desensitizing ionotropic receptors that mediate rapid but transient signalling, how they trigger intracellular signalling cascades is not well understood. In this review, we introduce the acidic microenvironment of tumours and the functional properties of ASICs, point out some conceptual problems, summarize reported roles of ASICs in different cancers, and highlight open questions on the mechanisms of their action in cancer cells. Finally, we propose guidelines to keep ASIC research in cancer on solid ground.
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Affiliation(s)
- Stefan Gründer
- Institute of Physiology, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
| | - Jakob Vanek
- Institute of Physiology, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
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Shi X, Liu R, Wang Y, Yu T, Zhang K, Zhang C, Gu Y, Zhang L, Wu J, Wang Q, Zhu F. Inhibiting acid-sensing ion channel exerts neuroprotective effects in experimental epilepsy via suppressing ferroptosis. CNS Neurosci Ther 2024; 30:e14596. [PMID: 38357854 PMCID: PMC10867794 DOI: 10.1111/cns.14596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 12/16/2023] [Accepted: 12/21/2023] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Epilepsy is a chronic neurological disease characterized by repeated and unprovoked epileptic seizures. Developing disease-modifying therapies (DMTs) has become important in epilepsy studies. Notably, focusing on iron metabolism and ferroptosis might be a strategy of DMTs for epilepsy. Blocking the acid-sensing ion channel 1a (ASIC1a) has been reported to protect the brain from ischemic injury by reducing the toxicity of [Ca2+ ]i . However, whether inhibiting ASIC1a could exert neuroprotective effects and become a novel target for DMTs, such as rescuing the ferroptosis following epilepsy, remains unknown. METHODS In our study, we explored the changes in ferroptosis-related indices, including glutathione peroxidase (GPx) enzyme activity and levels of glutathione (GSH), iron accumulation, lipid degradation products-malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) by collecting peripheral blood samples from adult patients with epilepsy. Meanwhile, we observed alterations in ASIC1a protein expression and mitochondrial microstructure in the epileptogenic foci of patients with drug-resistant epilepsy. Next, we accessed the expression and function changes of ASIC1a and measured the ferroptosis-related indices in the in vitro 0-Mg2+ model of epilepsy with primary cultured neurons. Subsequently, we examined whether blocking ASIC1a could play a neuroprotective role by inhibiting ferroptosis in epileptic neurons. RESULTS Our study first reported significant changes in ferroptosis-related indices, including reduced GPx enzyme activity, decreased levels of GSH, iron accumulation, elevated MDA and 4-HNE, and representative mitochondrial crinkling in adult patients with epilepsy, especially in epileptogenic foci. Furthermore, we found that inhibiting ASIC1a could produce an inhibitory effect similar to ferroptosis inhibitor Fer-1, alleviate oxidative stress response, and decrease [Ca2+ ]i overload by inhibiting the overexpressed ASIC1a in the in vitro epilepsy model induced by 0-Mg2+ . CONCLUSION Inhibiting ASIC1a has potent neuroprotective effects via alleviating [Ca2+ ]i overload and regulating ferroptosis on the models of epilepsy and may act as a promising intervention in DMTs.
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Affiliation(s)
- Xiaorui Shi
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
- China National Clinical Research Center for Neurological DiseasesBeijingChina
| | - Ru Liu
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
- China National Clinical Research Center for Neurological DiseasesBeijingChina
- Advanced Innovation Center for Human Brain ProtectionCapital Medical UniversityBeijingChina
| | - Yingting Wang
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
- China National Clinical Research Center for Neurological DiseasesBeijingChina
| | - Tingting Yu
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
- China National Clinical Research Center for Neurological DiseasesBeijingChina
| | - Kai Zhang
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Chao Zhang
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Yuyu Gu
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Limin Zhang
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Jianping Wu
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
- China National Clinical Research Center for Neurological DiseasesBeijingChina
- Advanced Innovation Center for Human Brain ProtectionCapital Medical UniversityBeijingChina
| | - Qun Wang
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
- China National Clinical Research Center for Neurological DiseasesBeijingChina
- Center of Epilepsy, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain DisordersCapital Medical UniversityBeijingChina
| | - Fei Zhu
- Department of Neurology, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
- China National Clinical Research Center for Neurological DiseasesBeijingChina
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Hori A, Fukazawa A, Katanosaka K, Mizuno M, Hotta N. Mechanosensitive channels in the mechanical component of the exercise pressor reflex. Auton Neurosci 2023; 250:103128. [PMID: 37925831 DOI: 10.1016/j.autneu.2023.103128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 10/24/2023] [Accepted: 10/26/2023] [Indexed: 11/07/2023]
Abstract
The cardiovascular response is appropriately regulated during exercise to meet the metabolic demands of the active muscles. The exercise pressor reflex is a neural feedback mechanism through thin-fiber muscle afferents activated by mechanical and metabolic stimuli in the active skeletal muscles. The mechanical component of this reflex is referred to as skeletal muscle mechanoreflex. Its initial step requires mechanotransduction mediated by mechanosensors, which convert mechanical stimuli into biological signals. Recently, various mechanosensors have been identified, and their contributions to muscle mechanoreflex have been actively investigated. Nevertheless, the mechanosensitive channels responsible for this muscular reflex remain largely unknown. This review discusses progress in our understanding of muscle mechanoreflex under healthy conditions, focusing on mechanosensitive channels.
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Affiliation(s)
- Amane Hori
- College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan; Japan Society for the Promotion of Science, 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-8472, Japan; Department of Applied Clinical Research, UT Southwestern Medical Center, Dallas, TX 75390-9174, USA
| | - Ayumi Fukazawa
- Japan Society for the Promotion of Science, 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-8472, Japan; Department of Applied Clinical Research, UT Southwestern Medical Center, Dallas, TX 75390-9174, USA
| | - Kimiaki Katanosaka
- College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan
| | - Masaki Mizuno
- Department of Applied Clinical Research, UT Southwestern Medical Center, Dallas, TX 75390-9174, USA
| | - Norio Hotta
- College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan.
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8
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Hajjar S, Zhou X. pH sensing at the intersection of tissue homeostasis and inflammation. Trends Immunol 2023; 44:807-825. [PMID: 37714775 PMCID: PMC10543622 DOI: 10.1016/j.it.2023.08.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 08/13/2023] [Accepted: 08/13/2023] [Indexed: 09/17/2023]
Abstract
pH is tightly maintained at cellular, tissue, and systemic levels, and altered pH - particularly in the acidic range - is associated with infection, injury, solid tumors, and physiological and pathological inflammation. However, how pH is sensed and regulated and how it influences immune responses remain poorly understood at the tissue level. Applying conceptual frameworks of homeostatic and inflammatory circuitries, we categorize cellular and tissue components engaged in pH regulation, drawing parallels from established cases in physiology. By expressing various intracellular (pHi) and extracellular pH (pHe)-sensing receptors, the immune system may integrate information on tissue and cellular states into the regulation of homeostatic and inflammatory programs. We introduce the novel concept of resistance and adaptation responses to rationalize pH-dependent immunomodulation intertwined with homeostatic equilibrium and inflammatory control. We discuss emerging challenges and opportunities in understanding the immunological roles of pH sensing, which might reveal new strategies to combat inflammation and restore tissue homeostasis.
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Affiliation(s)
- Stephanie Hajjar
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 300 Longwood Ave, Boston, MA 02115, USA
| | - Xu Zhou
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 300 Longwood Ave, Boston, MA 02115, USA.
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9
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Fischer L, Schmidt A, Dopychai A, Joussen S, Joeres N, Oslender-Bujotzek A, Schmalzing G, Gründer S. Physiologically relevant acid-sensing ion channel (ASIC) 2a/3 heteromers have a 1:2 stoichiometry. Commun Biol 2023; 6:701. [PMID: 37422581 PMCID: PMC10329638 DOI: 10.1038/s42003-023-05087-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 06/29/2023] [Indexed: 07/10/2023] Open
Abstract
Acid-sensing ion channels (ASICs) sense extracellular protons and are involved in synaptic transmission and pain sensation. ASIC1a and ASIC3 are the ASIC subunits with the highest proton sensitivity. ASIC2a in contrast has low proton sensitivity but increases the variability of ASICs by forming heteromers with ASIC1a or ASIC3. ASICs are trimers and for the ASIC1a/2a heteromer it has been shown that subunits randomly assemble with a flexible 1:2/2:1 stoichiometry. Both heteromers have almost identical proton sensitivity intermediate between ASIC1a and ASIC2a. Here, we investigated the stoichiometry of the ASIC2a/3 heteromer. Using electrophysiology, we extensively characterized, first, cells expressing ASIC2a and ASIC3 at different ratios, second, concatemeric channels with a fixed subunit stoichiometry, and, third, channels containing loss-of-functions mutations in specific subunits. Our results conclusively show that only ASIC2a/3 heteromers with a 1:2 stoichiometry had a proton-sensitivity intermediate between ASIC2a and ASIC3. In contrast, the proton sensitivity of ASIC2a/3 heteromers with a 2:1 stoichiometry was strongly acid-shifted by more than one pH unit, which suggests that they are not physiologically relevant. Together, our results reveal that the proton sensitivity of the two ASIC2a/3 heteromers is clearly different and that ASIC3 and ASIC1a make remarkably different contributions to heteromers with ASIC2a.
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Affiliation(s)
- Leon Fischer
- Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, D-52074, Aachen, Germany
- Department of Anesthesiology, Technical University Dresden, Dresden, Germany
| | - Axel Schmidt
- Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, D-52074, Aachen, Germany
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Anke Dopychai
- Institute of Clinical Pharmacology, RWTH Aachen University, Wendlingweg, D-52074, Aachen, Germany
| | - Sylvia Joussen
- Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, D-52074, Aachen, Germany
| | - Niko Joeres
- Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, D-52074, Aachen, Germany
- Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, D-52074, Aachen, Germany
| | | | - Günther Schmalzing
- Institute of Clinical Pharmacology, RWTH Aachen University, Wendlingweg, D-52074, Aachen, Germany
| | - Stefan Gründer
- Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, D-52074, Aachen, Germany.
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10
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Hung CH, Chin Y, Fong YO, Lee CH, Han DS, Lin JH, Sun WH, Chen CC. Acidosis-related pain and its receptors as targets for chronic pain. Pharmacol Ther 2023; 247:108444. [PMID: 37210007 DOI: 10.1016/j.pharmthera.2023.108444] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/24/2023] [Accepted: 05/15/2023] [Indexed: 05/22/2023]
Abstract
Sensing acidosis is an important somatosensory function in responses to ischemia, inflammation, and metabolic alteration. Accumulating evidence has shown that acidosis is an effective factor for pain induction and that many intractable chronic pain diseases are associated with acidosis signaling. Various receptors have been known to detect extracellular acidosis and all express in the somatosensory neurons, such as acid sensing ion channels (ASIC), transient receptor potential (TRP) channels and proton-sensing G-protein coupled receptors. In addition to sense noxious acidic stimulation, these proton-sensing receptors also play a vital role in pain processing. For example, ASICs and TRPs are involved in not only nociceptive activation but also anti-nociceptive effects as well as some other non-nociceptive pathways. Herein, we review recent progress in probing the roles of proton-sensing receptors in preclinical pain research and their clinical relevance. We also propose a new concept of sngception to address the specific somatosensory function of acid sensation. This review aims to connect these acid-sensing receptors with basic pain research and clinical pain diseases, thus helping with better understanding the acid-related pain pathogenesis and their potential therapeutic roles via the mechanism of acid-mediated antinociception.
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Affiliation(s)
- Chih-Hsien Hung
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yin Chin
- Department of Life Science & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-On Fong
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Han Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Der-Shen Han
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan
| | - Jiann-Her Lin
- Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Wei-Hsin Sun
- Department of Life Science & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Cheng Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan.
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11
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Animal toxins: As an alternative therapeutic target following ischemic stroke condition. Life Sci 2023; 317:121365. [PMID: 36640901 DOI: 10.1016/j.lfs.2022.121365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 11/29/2022] [Accepted: 12/31/2022] [Indexed: 01/13/2023]
Abstract
Globally, Ischemic stroke (IS) has become the second leading cause of mortality and chronic disability. The process of IS has triggered by the blockages of blood vessels to form clots in the brain which initiates multiple interactions with the key signaling pathways, counting excitotoxicity, acidosis, ionic imbalance, inflammation, oxidative stress, and neuronal dysfunction of cells, and ultimately cells going under apoptosis. Currently, FDA has approved only tissue plasminogen activator therapy, which is effective against IS with few limitations. However, the mechanism of excitotoxicity and acidosis has spurred the investigation of a potential candidate for IS therapy. Acid-sensing ion channels (ASICs) and Voltage-gated Ca2+ channels (VDCCs) get activated and disturb the brain's normal physiology. Animal toxins are novel inhibitors of ASICs and VDCCs channels and have provided neuroprotective insights into the pathophysiology of IS. This review will discuss the potential directions of translational ASICs and VDCCs inhibitors research for clinical therapies.
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12
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Sun HW, Chu XP, Simon RP, Xiong ZG, Leng TD. Inhibition of Acid-Sensing Ion Channels by KB-R7943, a Reverse Na+/Ca2+ Exchanger Inhibitor. Biomolecules 2023; 13:biom13030507. [PMID: 36979442 PMCID: PMC10046550 DOI: 10.3390/biom13030507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/27/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
KB-R7943, an isothiourea derivative, is widely used as a pharmacological inhibitor of reverse sodium–calcium exchanger (NCX). It has been shown to have neuroprotective and analgesic effects in animal models; however, the detailed molecular mechanisms remain elusive. In the current study, we investigated whether KB-R7943 modulates acid-sensing ion channels (ASICs), a group of proton-gated cation channels implicated in the pathophysiology of various neurological disorders, using the whole-cell patch clamp techniques. Our data show that KB-R7943 irreversibly inhibits homomeric ASIC1a channels heterologously expressed in Chinese Hamster Ovary (CHO) cells in a use- and concentration-dependent manner. It also reversibly inhibits homomeric ASIC2a and ASIC3 channels in CHO cells. Both the transient and sustained current components of ASIC3 are inhibited. Furthermore, KB-R7943 inhibits ASICs in primary cultured peripheral and central neurons. It inhibits the ASIC-like currents in mouse dorsal root ganglion (DRG) neurons and the ASIC1a-like currents in mouse cortical neurons. The inhibition of the ASIC1a-like current is use-dependent and unrelated to its effect on NCX since neither of the other two well-characterized NCX inhibitors, including SEA0400 and SN-6, shows an effect on ASIC. Our data also suggest that the isothiourea group, which is lacking in other structurally related analogs that do not affect ASIC1a-like current, may serve as a critical functional group. In summary, we characterize KB-R7943 as a new ASIC inhibitor. It provides a novel pharmacological tool for the investigation of the functions of ASICs and could serve as a lead compound for developing small-molecule drugs for treating ASIC-related disorders.
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Affiliation(s)
- Hua-Wei Sun
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Xiang-Ping Chu
- Department of Biomedical Sciences, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Roger P. Simon
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Zhi-Gang Xiong
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Tian-Dong Leng
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
- Correspondence:
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13
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Garcia SM, Naik JS, Resta TC, Jernigan NL. Acid-sensing ion channel 1a activates IKCa/SKCa channels and contributes to endothelium-dependent dilation. J Gen Physiol 2023; 155:e202213173. [PMID: 36484717 PMCID: PMC9984545 DOI: 10.1085/jgp.202213173] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 10/21/2022] [Accepted: 11/17/2022] [Indexed: 12/13/2022] Open
Abstract
Acid-sensing ion channel 1a (ASIC1a) belongs to a novel family of proton-gated cation channels that are permeable to both Na+ and Ca2+. ASIC1a is expressed in vascular smooth muscle and endothelial cells in a variety of vascular beds, yet little is known regarding the potential impact of ASIC1a to regulate local vascular reactivity. Our previous studies in rat mesenteric arteries suggest ASIC1a does not contribute to agonist-induced vasoconstriction but may mediate a vasodilatory response. The objective of the current study is to determine the role of ASIC1a in systemic vasodilatory responses by testing the hypothesis that the activation of endothelial ASIC1a mediates vasodilation of mesenteric resistance arteries through an endothelium-dependent hyperpolarization (EDH)-related pathway. The selective ASIC1a antagonist psalmotoxin 1 (PcTX1) largely attenuated the sustained vasodilatory response to acetylcholine (ACh) in isolated, pressurized mesenteric resistance arteries and ACh-mediated Ca2+ influx in freshly isolated mesenteric endothelial tubes. Similarly, basal tone was enhanced and ACh-induced vasodilation blunted in mesenteric arteries from Asic1a knockout mice. ASIC1a colocalizes with intermediate- and small-conductance Ca2+-activated K+ channels (IKCa and SKCa, respectively), and the IKCa/SKCa-sensitive component of the ACh-mediated vasodilation was blocked by ASIC1a inhibition. To determine the role of ASIC1a to activate IKCa/SKCa channels, we measured whole-cell K+ currents using the perforated-patch clamp technique in freshly isolated mesenteric endothelial cells. Inhibition of ASIC1a prevented ACh-induced activation of IKCa/SKCa channels. The ASIC1 agonist, α/β-MitTx, activated IKCa/SKCa channels and induced an IKCa/SKCa-dependent vasodilation. Together, the present study demonstrates that ASIC1a couples to IKCa/SKCa channels in mesenteric resistance arteries to mediate endothelium-dependent vasodilation.
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Affiliation(s)
- Selina M. Garcia
- Department of Cell Biology and Physiology University of New Mexico School of Medicine, Albuquerque, NM
| | - Jay S. Naik
- Department of Cell Biology and Physiology University of New Mexico School of Medicine, Albuquerque, NM
| | - Thomas C. Resta
- Department of Cell Biology and Physiology University of New Mexico School of Medicine, Albuquerque, NM
| | - Nikki L. Jernigan
- Department of Cell Biology and Physiology University of New Mexico School of Medicine, Albuquerque, NM
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14
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Jang W, Lim JY, Kang S, Kim M, Hwang SW, Kim C. Drosophila ppk19 encodes a proton-gated and mechanosensitive ion channel. Sci Rep 2022; 12:18346. [PMID: 36319833 PMCID: PMC9626565 DOI: 10.1038/s41598-022-23236-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 10/27/2022] [Indexed: 11/05/2022] Open
Abstract
In Drosophila larvae, nociceptive mdIV sensory neurons detect diverse noxious stimuli and prompt a nociceptive rolling response. Intriguingly, the same neurons also regulate stereotyped larval movement. The channels responsible for transducing these stimuli into electric signals are not yet fully identified. Here we undertook genetic and electrophysiological analysis of Ppk19, a member of the Deg/ENaC family of cationic channels. ppk19 mutants exhibited an impaired nociceptive rolling response upon mechanical force and acid, but no impairment in response to noxious temperature and gentle touch. Mutants also exhibited defective larval movement. RNAi against ppk19 in mdIV neurons likewise produced larvae with defects in mechanical and acid nociception and larval movement, but no impairment in detection of heat and gentle touch. Cultured cells transfected with ppk19 produced currents in acid and hypotonic solution, suggesting that ppk19 encodes an ion channel that responds to acid and cell swelling. Taken together, these findings suggest that Ppk19 acts in mdIV neurons as a proton- and mechano-gated ion channel to mediate acid- and mechano-responsive nociception and larval movement.
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Affiliation(s)
- Wijeong Jang
- grid.14005.300000 0001 0356 9399School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186 Korea
| | - Ji Yeon Lim
- grid.222754.40000 0001 0840 2678Department of Biomedical Sciences and Department of Physiology, Korea University College of Medicine, Seoul, 02841 Korea
| | - Seyoung Kang
- grid.14005.300000 0001 0356 9399School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186 Korea
| | - Minseok Kim
- grid.222754.40000 0001 0840 2678Department of Biomedical Sciences and Department of Physiology, Korea University College of Medicine, Seoul, 02841 Korea
| | - Sun Wook Hwang
- grid.222754.40000 0001 0840 2678Department of Biomedical Sciences and Department of Physiology, Korea University College of Medicine, Seoul, 02841 Korea
| | - Changsoo Kim
- grid.14005.300000 0001 0356 9399School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186 Korea
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15
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Joussain C, Le Coz O, Pichugin A, Marconi P, Lim F, Sicurella M, Foster K, Giuliano F, Epstein AL, Aranda Muñoz A. Development and Assessment of Herpes Simplex Virus Type 1 (HSV-1) Amplicon Vectors with Sensory Neuron-Selective Promoters. Int J Mol Sci 2022; 23:ijms23158474. [PMID: 35955608 PMCID: PMC9369297 DOI: 10.3390/ijms23158474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/20/2022] [Accepted: 07/26/2022] [Indexed: 02/01/2023] Open
Abstract
Background: Neurogenic detrusor overactivity (NDO) is a severe pathological condition characterized by involuntary detrusor contractions leading to urine leakage. This condition is frequent after spinal cord injury (SCI). Gene therapy for NDO requires the development of vectors that express therapeutic transgenes driven by sensory neuron-specific promoters. The aim of this study was to develop and assess tools for the characterization of sensory neuron-specific promoters in dorsal root ganglia (DRG) neurons after transduction with herpes simplex virus type 1 (HSV-1)-based amplicon defective vectors. Methods: The HSV-1 vector genome encoded two independent transcription cassettes: one expressed firefly luciferase (FLuc) driven by different promoters’ candidates (rTRPV1, rASIC3, rCGRP, or hCGRP), and the other expressed a reporter gene driven by an invariable promoter. The strength and selectivity of promoters was assessed in organotypic cultures of explanted adult DRG, or sympathetic and parasympathetic ganglia from control and SCI rats. Results: The rCGRP promoter induced selective expression in the DRG of normal rats. The rTRPV-1 promoter, which did not display selective activity in control rats, induced selective expression in DRG explanted from SCI rats. Conclusions: This study provides a methodology to assess sensory neuron-specific promoters, opening new perspectives for future gene therapy for NDO.
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Affiliation(s)
- Charles Joussain
- UMR INSERM U1179—Université de Versailles Saint Quentin en Yvelines/Paris Saclay, UFR des Sciences de la Santé Simone Veil, 2, Avenue de la Source de la Bièvre, 78180 Montigny-le-Bretonneux, France; (C.J.); (O.L.C.); (A.P.); (F.G.); (A.A.M.)
- Neuro-Urology R. Poincaré Hospital AP-HP, 104 bvd R. Poincaré, 92380 Garches, France
- Ipsen Innovation SAS, 5 Avenue du Canada, Zone Industrielle de Courtaboeuf, 91940 Les Ulis, France
| | - Olivier Le Coz
- UMR INSERM U1179—Université de Versailles Saint Quentin en Yvelines/Paris Saclay, UFR des Sciences de la Santé Simone Veil, 2, Avenue de la Source de la Bièvre, 78180 Montigny-le-Bretonneux, France; (C.J.); (O.L.C.); (A.P.); (F.G.); (A.A.M.)
| | - Andrey Pichugin
- UMR INSERM U1179—Université de Versailles Saint Quentin en Yvelines/Paris Saclay, UFR des Sciences de la Santé Simone Veil, 2, Avenue de la Source de la Bièvre, 78180 Montigny-le-Bretonneux, France; (C.J.); (O.L.C.); (A.P.); (F.G.); (A.A.M.)
| | - Peggy Marconi
- Department of Chemical, Pharmaceutical and Agricultural Sciences (DOCPAS), Via Luigi Borsari, 44121 Ferrara, Italy; (P.M.); (M.S.)
| | - Filip Lim
- Centro de Biologia Molecular Severo Ochoa, Universidad Autonoma de Madrid (UAM), CSIC-UAM, Calle Nicolas Cabrera 1, Cantoblanco, 28049 Madrid, Spain;
| | - Mariaconcetta Sicurella
- Department of Chemical, Pharmaceutical and Agricultural Sciences (DOCPAS), Via Luigi Borsari, 44121 Ferrara, Italy; (P.M.); (M.S.)
- IRCCS Ospedale San Raffaele, Urological Research Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Keith Foster
- Ipsen Bioinnovation Ltd., 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK;
| | - François Giuliano
- UMR INSERM U1179—Université de Versailles Saint Quentin en Yvelines/Paris Saclay, UFR des Sciences de la Santé Simone Veil, 2, Avenue de la Source de la Bièvre, 78180 Montigny-le-Bretonneux, France; (C.J.); (O.L.C.); (A.P.); (F.G.); (A.A.M.)
- Neuro-Urology R. Poincaré Hospital AP-HP, 104 bvd R. Poincaré, 92380 Garches, France
| | - Alberto L. Epstein
- UMR INSERM U1179—Université de Versailles Saint Quentin en Yvelines/Paris Saclay, UFR des Sciences de la Santé Simone Veil, 2, Avenue de la Source de la Bièvre, 78180 Montigny-le-Bretonneux, France; (C.J.); (O.L.C.); (A.P.); (F.G.); (A.A.M.)
- EG427, Pépinière Hôpital Cochin, 29 Rue du Faubourg Saint-Jacques, 75014 Paris, France
- Correspondence:
| | - Alejandro Aranda Muñoz
- UMR INSERM U1179—Université de Versailles Saint Quentin en Yvelines/Paris Saclay, UFR des Sciences de la Santé Simone Veil, 2, Avenue de la Source de la Bièvre, 78180 Montigny-le-Bretonneux, France; (C.J.); (O.L.C.); (A.P.); (F.G.); (A.A.M.)
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16
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Majagi S, Mangat S, Chu XP. Commentary: Pharmacological Validation of ASIC1a as a Druggable Target for Neuroprotection in Cerebral Ischemia Using an Intravenously Available Small Molecule Inhibitor. Front Pharmacol 2022; 13:938748. [PMID: 35865964 PMCID: PMC9294732 DOI: 10.3389/fphar.2022.938748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 06/16/2022] [Indexed: 11/23/2022] Open
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17
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Zhang L, Zheng L, Yang X, Yao S, Wang H, An J, Jin H, Wen G, Tuo B. Pathology and physiology of acid‑sensitive ion channels in the digestive system (Review). Int J Mol Med 2022; 50:94. [PMID: 35616162 PMCID: PMC9170189 DOI: 10.3892/ijmm.2022.5150] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/11/2022] [Indexed: 11/16/2022] Open
Abstract
As a major proton-gated cation channel, acid-sensitive ion channels (ASICs) can perceive large extracellular pH changes. ASICs play an important role in the occurrence and development of diseases of various organs and tissues including in the heart, brain, and gastrointestinal tract, as well as in tumor proliferation, invasion, and metastasis in acidosis and regulation of an acidic microenvironment. The permeability of ASICs to sodium and calcium ions is the basis of their physiological and pathological roles in the body. This review summarizes the physiological and pathological mechanisms of ASICs in digestive system diseases, which plays an important role in the early diagnosis, treatment, and prognosis of digestive system diseases related to ASIC expression.
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Affiliation(s)
- Li Zhang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Liming Zheng
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Xingyue Yang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Shun Yao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Hui Wang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jiaxing An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Hai Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Guorong Wen
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
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18
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Wei S, Liu TT, Hu WP, Qiu CY. Resveratrol inhibits the activity of acid-sensing ion channels in male rat dorsal root ganglion neurons. J Neurosci Res 2022; 100:1755-1764. [PMID: 35592934 DOI: 10.1002/jnr.25060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/16/2022] [Accepted: 04/22/2022] [Indexed: 11/07/2022]
Abstract
Resveratrol can relieve pain under various pain conditions. One of the mechanisms of resveratrol analgesia is the regulation of ion channels. Acid-sensing ion channels (ASICs) are expressed predominantly in nociceptive sensory neurons to detect changes in extracellular pH. ASICs are important players in pain associated with tissue acidification. However, it is still unclear whether ASICs are resveratrol targets. Electrophysiological recordings showed that resveratrol decreased acid-induced and ASIC-mediated currents in male rat dorsal root ganglion (DRG) neurons in a concentration-dependent manner. Resveratrol downwardly shifted the concentration-response curve for protons, suggesting that it inhibited ASICs not by changing the pH0.5 , but by suppressing the proton-induced maximum response. It also suppressed acid-triggered action potentials in the rat DRG neurons. Finally, intraplantar pretreatment with resveratrol relieved acid-induced nociceptive responses in male rats in a dose-dependent manner. These results indicated that resveratrol inhibited ASIC-mediated electrophysiological activity and nociception, suggesting a novel peripheral mechanism underlying its analgesic effect.
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Affiliation(s)
- Shuang Wei
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China.,School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China
| | - Ting-Ting Liu
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China
| | - Wang-Ping Hu
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China.,Department of Physiology, Hubei College of Chinese Medicine, Jingzhou, PR China
| | - Chun-Yu Qiu
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China.,School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China
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19
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Wei S, Hao JW, Qiao WL, Li Q, Liu TT, Qiu CY, Hu WP. Suppression of ASIC activity by the activation of A1 adenosine receptors in rat primary sensory neurons. Neuropharmacology 2021; 205:108924. [PMID: 34919904 DOI: 10.1016/j.neuropharm.2021.108924] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/21/2021] [Accepted: 12/10/2021] [Indexed: 11/25/2022]
Abstract
Peripheral A1 adenosine receptor signaling has been shown to have analgesic effects in a variety of pain conditions. However, it is not yet fully elucidated for the precise molecular mechanisms. Acid sensing ion channels (ASICs) are expressed predominantly in nociceptive sensory neurons responding to protons. Given that both A1 adenosine receptors and ASICs are present in dorsal root ganglia (DRG) neurons, we therefore investigated whether there was a cross-talk between the two types of receptors. Herein, electrophysiological recordings showed that the A1 adenosine receptor agonist N6-cyclopentyladenosine (CPA) suppressed acid-induced currents and action potentials, which were mediated by ASICs, in rat DRG neurons. CPA inhibited the maximum response to protons, as shown a downward shift of concentration-response curve for protons. The CPA-induced suppression of ASIC currents was blocked by the A1 adenosine receptor antagonist KW-3902 and also prevented by intracellular application of the Gi/o-protein inhibitor pertussis toxin, the adenylate cyclase activator forskolin, and the cAMP analog 8-Br-cAMP. Finally, intraplantar pretreatment of CPA dose-dependently relieved acid-induced nociceptive responses in rats through peripheral A1 adenosine receptors. These results suggested that CPA suppressed ASICs via A1 adenosine receptors and intracellular Gi/o-proteins and cAMP signaling cascades in rat DRG neurons, which was a novel potential mechanism underlying analgesia of peripheral A1 adenosine receptors.
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Affiliation(s)
- Shuang Wei
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, PR China
| | - Jia-Wei Hao
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, PR China
| | - Wen-Long Qiao
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, PR China
| | - Qing Li
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, PR China
| | - Ting-Ting Liu
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, PR China
| | - Chun-Yu Qiu
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, PR China
| | - Wang-Ping Hu
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, PR China; Hubei College of Chinese Medicine, 87 Xueyuan Road, Jingzhou, 434020, Hubei, PR China.
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20
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Dulai JS, Smith ESJ, Rahman T. Acid-sensing ion channel 3: An analgesic target. Channels (Austin) 2021; 15:94-127. [PMID: 33258401 PMCID: PMC7801124 DOI: 10.1080/19336950.2020.1852831] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 11/13/2020] [Indexed: 12/12/2022] Open
Abstract
Acid-sensing ion channel 3 (ASIC3) belongs to the epithelial sodium channel/degenerin (ENaC/DEG) superfamily. There are 7 different ASIC subunits encoded by 5 different genes. Most ASIC subunits form trimeric ion channels that upon activation by extracellular protons mediate a transient inward current inducing cellular excitability. ASIC subunits exhibit differential tissue expression and biophysical properties, and the ability of subunits to form homo- and heteromeric trimers further increases the complexity of currents measured and their pharmacological properties. ASIC3 is of particular interest, not only because it exhibits high expression in sensory neurones, but also because upon activation it does not fully inactivate: a transient current is followed by a sustained current that persists during a period of extracellular acidity, i.e. ASIC3 can encode prolonged acidosis as a nociceptive signal. Furthermore, certain mediators sensitize ASIC3 enabling smaller proton concentrations to activate it and other mediators can directly activate the channel at neutral pH. Moreover, there is a plethora of evidence using transgenic mouse models and pharmacology, which supports ASIC3 as being a potential target for development of analgesics. This review will focus on current understanding of ASIC3 function to provide an overview of how ASIC3 contributes to physiology and pathophysiology, examining the mechanisms by which it can be modulated, and highlighting gaps in current understanding and future research directions.
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Affiliation(s)
| | | | - Taufiq Rahman
- Department of Pharmacology, University of Cambridge, Cambridge, UK
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21
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Bachmann M, Ortega-Ramírez A, Leisle L, Gründer S. Efficient expression of a cnidarian peptide-gated ion channel in mammalian cells. Channels (Austin) 2021; 15:273-283. [PMID: 33522420 PMCID: PMC7889164 DOI: 10.1080/19336950.2021.1882762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/25/2021] [Accepted: 01/25/2021] [Indexed: 10/24/2022] Open
Abstract
Hydra Na+ channels (HyNaCs) are peptide-gated ion channels of the DEG/ENaC gene family that are directly activated by neuropeptides of the Hydra nervous system. They have previously been successfully characterized in Xenopus oocytes. To establish their expression in mammalian cells, we transiently expressed heteromeric HyNaC2/3/5 in human HEK 293 and monkey COS-7 cells. We found that the expression of HyNaC2/3/5 using native cDNAs was inefficient and that codon optimization strongly increased protein expression and current amplitude in patch-clamp experiments. We used the improved expression of codon-optimized channel subunits to perform Ca2+ imaging and to demonstrate their glycosylation pattern. In summary, we established efficient expression of a cnidarian ion channel in mammalian cell lines.
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Affiliation(s)
- Michèle Bachmann
- Department of Physiology, RWTH Aachen University, Aachen, Germany
| | | | - Lilia Leisle
- Department of Physiology, RWTH Aachen University, Aachen, Germany
| | - Stefan Gründer
- Department of Physiology, RWTH Aachen University, Aachen, Germany
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22
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Duzhyy DE, Voitenko NV, Belan PV. Peripheral Inflammation Results in Increased Excitability of Capsaicin-Insensitive Nociceptive DRG Neurons Mediated by Upregulation of ASICs and Voltage-Gated Ion Channels. Front Cell Neurosci 2021; 15:723295. [PMID: 34733139 PMCID: PMC8558483 DOI: 10.3389/fncel.2021.723295] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 09/17/2021] [Indexed: 11/13/2022] Open
Abstract
Previously, we have characterized the capsaicin-insensitive low pH-sensitive (caps−lpH+) subtype of small-sized nociceptive dorsal root ganglion (DRG) neurons that express acid-sensing ion channels, T-type Ca2+ channels, and have isolectin B4-negative phenotype. These neurons demonstrated increased excitability in a model of long-term diabetes, contributing to chronic pain sensation. Here we studied changes in the excitability of the caps−lpH+ neurons and underlying changes in the functional expression and gating properties of ion channels under complete Freund's adjuvant (CFA)-induced peripheral inflammation. We have found that, under these pathological conditions, the functional expression of the acid-sensing ion channels (ASICs) and voltage-gated Na+ channels, was increased. In addition, T-type Ca2+ current was significantly increased in the neurons at the membrane potentials close to its resting value. Altogether, the observed changes in the channel functioning shifted a pH level evoking an action potential (AP) toward its physiological value and led to an increase of evoked and spontaneous excitability of the caps−lpH+ neurons that may contribute to hyperalgesia and chronic inflammatory pain.
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Affiliation(s)
- Dmytro E Duzhyy
- Department of Sensory Signaling, Bogomoletz Institute of Physiology, Kyiv, Ukraine
| | - Nana V Voitenko
- Department of Sensory Signaling, Bogomoletz Institute of Physiology, Kyiv, Ukraine.,Department of Molecular Physiology and Biophysics, Kyiv Academic University, Kyiv, Ukraine.,Research Center, Dobrobut Academy, Kyiv, Ukraine
| | - Pavel V Belan
- Research Center, Dobrobut Academy, Kyiv, Ukraine.,Department of Molecular Biophysics, Bogomoletz Institute of Physiology, Kyiv, Ukraine
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Montalbetti N, Carattino MD. Acid-sensing ion channels modulate bladder nociception. Am J Physiol Renal Physiol 2021; 321:F587-F599. [PMID: 34514879 PMCID: PMC8813206 DOI: 10.1152/ajprenal.00302.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/30/2021] [Accepted: 09/07/2021] [Indexed: 01/23/2023] Open
Abstract
Sensitization of neuronal pathways and persistent afferent drive are major contributors to somatic and visceral pain. However, the underlying mechanisms that govern whether afferent signaling will give rise to sensitization and pain are not fully understood. In the present report, we investigated the contribution of acid-sensing ion channels (ASICs) to bladder nociception in a model of chemical cystitis induced by cyclophosphamide (CYP). We found that the administration of CYP to mice lacking ASIC3, a subunit primarily expressed in sensory neurons, generates pelvic allodynia at a time point at which only modest changes in pelvic sensitivity are apparent in wild-type mice. The differences in mechanical pelvic sensitivity between wild-type and Asic3 knockout mice treated with CYP were ascribed to sensitized bladder C nociceptors. Deletion of Asic3 from bladder sensory neurons abolished their ability to discharge action potentials in response to extracellular acidification. Collectively, the results of our study support the notion that protons and their cognate ASIC receptors are part of a mechanism that operates at the nerve terminals to control nociceptor excitability and sensitization.NEW & NOTEWORTHY Our study indicates that protons and their cognate acid-sensing ion channel receptors are part of a mechanism that operates at bladder afferent terminals to control their function and that the loss of this regulatory mechanism results in hyperactivation of nociceptive pathways and the development of pain in the setting of chemical-induced cystitis.
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Affiliation(s)
- Nicolas Montalbetti
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Marcelo D Carattino
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
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24
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Mango D, Nisticò R. Neurodegenerative Disease: What Potential Therapeutic Role of Acid-Sensing Ion Channels? Front Cell Neurosci 2021; 15:730641. [PMID: 34690702 PMCID: PMC8531221 DOI: 10.3389/fncel.2021.730641] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 09/15/2021] [Indexed: 12/19/2022] Open
Abstract
Acidic pH shift occurs in many physiological neuronal activities such as synaptic transmission and synaptic plasticity but also represents a characteristic feature of many pathological conditions including inflammation and ischemia. Neuroinflammation is a complex process that occurs in various neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease. Acid-sensing ion channels (ASICs) represent a widely expressed pH sensor in the brain that play a key role in neuroinflammation. On this basis, acid-sensing ion channel blockers are able to exert neuroprotective effects in different neurodegenerative diseases. In this review, we discuss the multifaceted roles of ASICs in brain physiology and pathology and highlight ASIC1a as a potential pharmacological target in neurodegenerative diseases.
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Affiliation(s)
- Dalila Mango
- Laboratory of Pharmacology of Synaptic Plasticity, European Brain Research Institute, Rome, Italy.,School of Pharmacy, University of Rome "Tor Vergata", Rome, Italy
| | - Robert Nisticò
- Laboratory of Pharmacology of Synaptic Plasticity, European Brain Research Institute, Rome, Italy.,School of Pharmacy, University of Rome "Tor Vergata", Rome, Italy
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25
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Foster VS, Rash LD, King GF, Rank MM. Acid-Sensing Ion Channels: Expression and Function in Resident and Infiltrating Immune Cells in the Central Nervous System. Front Cell Neurosci 2021; 15:738043. [PMID: 34602982 PMCID: PMC8484650 DOI: 10.3389/fncel.2021.738043] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/30/2021] [Indexed: 11/15/2022] Open
Abstract
Peripheral and central immune cells are critical for fighting disease, but they can also play a pivotal role in the onset and/or progression of a variety of neurological conditions that affect the central nervous system (CNS). Tissue acidosis is often present in CNS pathologies such as multiple sclerosis, epileptic seizures, and depression, and local pH is also reduced during periods of ischemia following stroke, traumatic brain injury, and spinal cord injury. These pathological increases in extracellular acidity can activate a class of proton-gated channels known as acid-sensing ion channels (ASICs). ASICs have been primarily studied due to their ubiquitous expression throughout the nervous system, but it is less well recognized that they are also found in various types of immune cells. In this review, we explore what is currently known about the expression of ASICs in both peripheral and CNS-resident immune cells, and how channel activation during pathological tissue acidosis may lead to altered immune cell function that in turn modulates inflammatory pathology in the CNS. We identify gaps in the literature where ASICs and immune cell function has not been characterized, such as neurotrauma. Knowledge of the contribution of ASICs to immune cell function in neuropathology will be critical for determining whether the therapeutic benefits of ASIC inhibition might be due in part to an effect on immune cells.
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Affiliation(s)
- Victoria S. Foster
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Lachlan D. Rash
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Glenn F. King
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, St Lucia, QLD, Australia
| | - Michelle M. Rank
- Anatomy and Physiology, Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
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Native expression of ASIC1a and ASIC1b human homologues in the HEK 293 cell line allows pharmacological evaluation of analgesics targeting acid sensation in humans. Neuroreport 2021; 31:865-870. [PMID: 32453026 DOI: 10.1097/wnr.0000000000001465] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Nociceptors arising from the dorsal root ganglia (DRG) express acid-sensing ion channel-1 (ASIC1) subtypes to mediate the perception of inflammatory and neuropathic pain, and as such, these receptors are attractive targets for the development of analgesics for these painful conditions. Nevertheless, given that the human and rodent DRG differ considerably in subtype proportions of ASIC1 and that the pharmacological properties of rodent ASIC1 subtypes and their human homologues are distinct, ASIC1 inhibitors that demonstrate analgesic properties in rodents may not necessarily be effective in preventing pain in humans. In this study, we show that human embryonic kidney (HEK) 293 cells, which are routinely used as a cellular vehicle for the heterologous expression and pharmacological characterization of receptors and ion channels, natively transcribe the human homologues of ASIC1a and ASIC1b at similar proportions to those found in the human DRG. Importantly, HEK 293 ASIC1 is sensitive to inhibition by amiloride, ethylisopropyl amiloride, and the snake toxin mambalgin-1, but insensitive to inhibition by the ASIC1a inhibitor psalmotoxin-1 when applied at a physiological conditioning pH. Given that the human DRG transcribes the same set of ASIC1 subtypes as HEK 293 cells, our data support the notion that mambalgin-1 may be effective against acid pain sensation in humans. Moreover, our data suggest that the HEK 293 cell line may be a suitable tool for pharmacological screening and characterization of heteromeric human ASIC1.
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Mambalgin-3 potentiates human acid-sensing ion channel 1b under mild to moderate acidosis: Implications as an analgesic lead. Proc Natl Acad Sci U S A 2021; 118:2021581118. [PMID: 33602819 PMCID: PMC7923528 DOI: 10.1073/pnas.2021581118] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Acid-sensing ion channels (ASICs) are expressed in the nervous system, activated by acidosis, and implicated in pain pathways. Mambalgins are peptide inhibitors of ASIC1 and analgesic in rodents via inhibition of centrally expressed ASIC1a and peripheral ASIC1b. This activity has generated interest in mambalgins as potential therapeutics. However, most mechanism and structure–activity relationship work on mambalgins has focused on ASIC1a, and neglected the peripheral analgesic target ASIC1b. Here, we compare mambalgin potency and mechanism of action at heterologously expressed rat and human ASIC1 variants. Unlike the nanomolar inhibition at ASIC1a and rodent ASIC1b, we find mambalgin-3 only weakly inhibits human ASIC1b and ASIC1b/3 under severe acidosis, but potentiates currents under mild/moderate acidosis. Our data highlight the importance of understanding the activity of potential ASIC-targeting pharmaceuticals at human channels.
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28
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Yamamoto T, Mulpuri Y, Izraylev M, Li Q, Simonian M, Kramme C, Schmidt BL, Seltzman HH, Spigelman I. Selective targeting of peripheral cannabinoid receptors prevents behavioral symptoms and sensitization of trigeminal neurons in mouse models of migraine and medication overuse headache. Pain 2021; 162:2246-2262. [PMID: 33534356 PMCID: PMC8277668 DOI: 10.1097/j.pain.0000000000002214] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/19/2021] [Indexed: 01/03/2023]
Abstract
ABSTRACT Migraine affects ∼15% of the world's population greatly diminishing their quality of life. Current preventative treatments are effective in only a subset of migraine patients, and although cannabinoids seem beneficial in alleviating migraine symptoms, central nervous system side effects limit their widespread use. We developed peripherally restricted cannabinoids (PRCBs) that relieve chronic pain symptoms of cancer and neuropathies, without appreciable central nervous system side effects or tolerance development. Here, we determined PRCB effectiveness in alleviating hypersensitivity symptoms in mouse models of migraine and medication overuse headache. Long-term glyceryl trinitrate (GTN, 10 mg/kg) administration led to increased sensitivity to mechanical stimuli and increased expression of phosphorylated protein kinase A, neuronal nitric oxide synthase, and transient receptor potential ankyrin 1 proteins in trigeminal ganglia. Peripherally restricted cannabinoid pretreatment, but not posttreatment, prevented behavioral and biochemical correlates of GTN-induced sensitization. Low pH-activated and allyl isothiocyanate-activated currents in acutely isolated trigeminal neurons were reversibly attenuated by PRCB application. Long-term GTN treatment significantly enhanced these currents. Long-term sumatriptan treatment also led to the development of allodynia to mechanical and cold stimuli that was slowly reversible after sumatriptan discontinuation. Subsequent challenge with a previously ineffective low-dose GTN (0.1-0.3 mg/kg) revealed latent behavioral sensitization and increased expression of phosphorylated protein kinase A, neuronal nitric oxide synthase, and transient receptor potential ankyrin 1 proteins in trigeminal ganglia. Peripherally restricted cannabinoid pretreatment prevented all behavioral and biochemical correlates of allodynia and latent sensitization. Importantly, long-term PRCB treatment alone did not produce any behavioral or biochemical signs of sensitization. These data validate peripheral cannabinoid receptors as potential therapeutic targets in migraine and medication overuse headache.
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Affiliation(s)
- Toru Yamamoto
- Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA
| | - Yatendra Mulpuri
- Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA
| | - Mikhail Izraylev
- Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA
| | - Qianyi Li
- Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA
| | - Menooa Simonian
- Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA
| | - Christian Kramme
- Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA
| | - Brian L. Schmidt
- Department of Oral & Maxillofacial Surgery and Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY
| | - Herbert H. Seltzman
- Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC
| | - Igor Spigelman
- Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA
- Brain Research Institute, University of California, Los Angeles, Los Angeles, CA
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29
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Tang J, Su Q, Zhang X, Qin W, Liu H, Liang M, Yu C. Brain Gene Expression Pattern Correlated with the Differential Brain Activation by Pain and Touch in Humans. Cereb Cortex 2021; 31:3506-3521. [PMID: 33693675 DOI: 10.1093/cercor/bhab028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/04/2021] [Accepted: 01/21/2021] [Indexed: 12/26/2022] Open
Abstract
Genes involved in pain and touch sensations have been studied extensively, but very few studies have tried to link them with neural activities in the brain. Here, we aimed to identify genes preferentially correlated to painful activation patterns by linking the spatial patterns of gene expression of Allen Human Brain Atlas with the pain-elicited neural responses in the human brain, with a parallel, control analysis for identification of genes preferentially correlated to tactile activation patterns. We identified 1828 genes whose expression patterns preferentially correlated to painful activation patterns and 411 genes whose expression patterns preferentially correlated to tactile activation pattern at the cortical level. In contrast to the enrichment for astrocyte and inhibitory synaptic transmission of genes preferentially correlated to tactile activation, the genes preferentially correlated to painful activation were mainly enriched for neuron and opioid- and addiction-related pathways and showed significant overlap with pain-related genes identified in previous studies. These findings not only provide important evidence for the differential genetic architectures of specific brain activation patterns elicited by painful and tactile stimuli but also validate a new approach to studying pain- and touch-related genes more directly from the perspective of neural responses in the human brain.
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Affiliation(s)
- Jie Tang
- Tianjin Key Laboratory of Functional Imaging, Department of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Qian Su
- Tianjin Key Laboratory of Cancer Prevention and Therapy, Department of Molecular Imaging and Nuclear Medicine, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for China, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Xue Zhang
- Tianjin Key Laboratory of Functional Imaging, Department of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Wen Qin
- Tianjin Key Laboratory of Functional Imaging, Department of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Huaigui Liu
- Tianjin Key Laboratory of Functional Imaging, Department of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Meng Liang
- Tianjin Key Laboratory of Functional Imaging, School of Medical Imaging, Tianjin Medical University, Tianjin 300052, P.R. China
| | - Chunshui Yu
- Tianjin Key Laboratory of Functional Imaging, Department of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.,CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, P.R. China
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30
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Citric Acid in Drug Formulations Causes Pain by Potentiating Acid-Sensing Ion Channel 1. J Neurosci 2021; 41:4596-4606. [PMID: 33888605 PMCID: PMC8260239 DOI: 10.1523/jneurosci.2087-20.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 12/08/2020] [Accepted: 04/10/2021] [Indexed: 11/21/2022] Open
Abstract
Pain at the injection site is a common complaint of patients receiving therapeutic formulations containing citric acid. Despite the widely acknowledged role of acid-sensing ion channels (ASICs) in acid-related perception, the specific ASIC subtype mediating pain caused by subcutaneous acid injection and the mechanism by which citrate affects this process are less clear. Here, male mice subjected to intraplantar acid injection responded by executing a withdrawal reflex, and this response was abolished by ASIC1 but not ASIC2 knockout. Although intraplantar injection of neutral citrate solution did not produce this response, intraplantar injection of acidic citrate solution produced a withdrawal reflex greater than that produced by acidity alone. Consistent with the behavioral data, neutral citrate failed to produce an electrophysiological response in HEK293 cells, which express ASIC1, but acidic citrate produced a whole-cell inward current greater than that produced by acidity alone. Saturating the intracellular solution with citrate had no effect on the potentiating effect of extracellular citrate, suggesting that citrate acted extracellularly to potentiate ASIC1. Moreover, exposure to citrate immediately before acid stimulation failed to potentiate ASIC1 currents, which ruled out the involvement of a metabotropic receptor gated by a citrate metabolite. Finally, removal of calcium ions from the extracellular solution mimicked the potentiating effect of citrate and prevented citrate from further potentiating ASIC1. Our data demonstrate that ASIC1 is necessary for the nociceptive response caused by subcutaneous acid infusion and that neutral citrate, despite not inducing ASIC1 currents or nociceptive behavior on its own, potentiates acid nociception by removing the inhibitory effect of extracellular calcium ions on ASIC1. SIGNIFICANCE STATEMENT Citric acid is a common ingredient used in pharmaceutical formulations. Despite the widespread clinical use of these formulations, it remains unclear how citric acid causes pain when injected into patients. We identified ASIC1 as the key receptor used to detect injection-site pain caused by acid, and we showed that neutral citrate does not stimulate ASIC1; instead, citrate substantially potentiates ASIC1 activation when injected simultaneously with acid. In addition, we demonstrated that citrate potentiates ASIC1 by removing the inhibitory action of calcium on the extracellular side of the receptor. Given that injection-site pain is the primary complaint of patients receiving citrate-containing medical products, our data provide mechanistic insight into a common medical complaint and suggest a means of avoiding injection pain.
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31
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Wei X, Wang L, Hua J, Jin XH, Ji F, Peng K, Zhou B, Yang J, Meng XW. Inhibiting BDNF/TrkB.T1 receptor improves resiniferatoxin-induced postherpetic neuralgia through decreasing ASIC3 signaling in dorsal root ganglia. J Neuroinflammation 2021; 18:96. [PMID: 33874962 PMCID: PMC8054387 DOI: 10.1186/s12974-021-02148-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 04/03/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Postherpetic neuralgia (PHN) is a devastating complication after varicella-zoster virus infection. Brain-derived neurotrophic factor (BDNF) has been shown to participate in the pathogenesis of PHN. A truncated isoform of the tropomyosin receptor kinase B (TrkB) receptor TrkB.T1, as a high-affinity receptor of BDNF, is upregulated in multiple nervous system injuries, and such upregulation is associated with pain. Acid-sensitive ion channel 3 (ASIC3) is involved in chronic neuropathic pain, but its relation with BDNF/TrkB.T1 in the peripheral nervous system (PNS) during PHN is unclear. This study aimed to investigate whether BDNF/TrkB.T1 contributes to PHN through regulating ASIC3 signaling in dorsal root ganglia (DRGs). METHODS Resiniferatoxin (RTX) was used to induce rat PHN models. Mechanical allodynia was assessed by measuring the paw withdrawal thresholds (PWTs). Thermal hyperalgesia was determined by detecting the paw withdrawal latencies (PWLs). We evaluated the effects of TrkB.T1-ASIC3 signaling inhibition on the behavior, neuronal excitability, and inflammatory response during RTX-induced PHN. ASIC3 short hairpin RNA (shRNA) transfection was used to investigate the effect of exogenous BDNF on inflammatory response in cultured PC-12 cells. RESULTS RTX injection induced mechanical allodynia and upregulated the protein expression of BDNF, TrkB.T1, ASIC3, TRAF6, nNOS, and c-Fos, as well as increased neuronal excitability in DRGs. Inhibition of ASIC3 reversed the abovementioned effects of RTX, except for BDNF and TrkB.T1 protein expression. In addition, inhibition of TrkB.T1 blocked RTX-induced mechanical allodynia, activation of ASIC3 signaling, and hyperexcitability of neurons. RTX-induced BDNF upregulation was found in both neurons and satellite glia cells in DRGs. Furthermore, exogenous BDNF activated ASIC3 signaling, increased NO level, and enhanced IL-6, IL-1β, and TNF-α levels in PC-12 cells, which was blocked by shRNA-ASIC3 transfection. CONCLUSION These findings demonstrate that inhibiting BDNF/TrkB.T1 reduced inflammation, decreased neuronal hyperexcitability, and improved mechanical allodynia through regulating the ASIC3 signaling pathway in DRGs, which may provide a novel therapeutic target for patients with PHN.
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Affiliation(s)
- Xiang Wei
- Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China
| | - Lina Wang
- Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China
| | - Jie Hua
- Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China
| | - Xiao-Hong Jin
- Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China
| | - Fuhai Ji
- Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China
| | - Ke Peng
- Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China
| | - Bin Zhou
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China.,Jiangsu Key Laboratory of Gastrointestinal tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jianping Yang
- Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China.
| | - Xiao-Wen Meng
- Department of Anesthesiology and Pain Management, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, China.
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32
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Abbott SBG, Souza GMPR. Chemoreceptor mechanisms regulating CO 2 -induced arousal from sleep. J Physiol 2021; 599:2559-2571. [PMID: 33759184 DOI: 10.1113/jp281305] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/16/2021] [Indexed: 12/24/2022] Open
Abstract
Arousal from sleep in response to CO2 is a life-preserving reflex that enhances ventilatory drive and facilitates behavioural adaptations to restore eupnoeic breathing. Recurrent activation of the CO2 -arousal reflex is associated with sleep disruption in obstructive sleep apnoea. In this review we examine the role of chemoreceptors in the carotid bodies, the retrotrapezoid nucleus and serotonergic neurons in the dorsal raphe in the CO2 -arousal reflex. We also provide an overview of the supra-medullary structures that mediate CO2 -induced arousal. We propose a framework for the CO2 -arousal reflex in which the activity of the chemoreceptors converges in the parabrachial nucleus to trigger cortical arousal.
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Affiliation(s)
- Stephen B G Abbott
- Department of Pharmacology, University of Virginia, Charlottesville, VA, 29903, USA
| | - George M P R Souza
- Department of Pharmacology, University of Virginia, Charlottesville, VA, 29903, USA
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33
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Costa FV, Rosa LV, Quadros VA, de Abreu MS, Santos ARS, Sneddon LU, Kalueff AV, Rosemberg DB. The use of zebrafish as a non-traditional model organism in translational pain research: the knowns and the unknowns. Curr Neuropharmacol 2021; 20:476-493. [PMID: 33719974 DOI: 10.2174/1570159x19666210311104408] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 02/24/2021] [Accepted: 02/28/2021] [Indexed: 11/22/2022] Open
Abstract
The ability of the nervous system to detect a wide range of noxious stimuli is crucial to avoid life-threatening injury and to trigger protective behavioral and physiological responses. Pain represents a complex phenomenon, including nociception associated with cognitive and emotional processing. Animal experimental models have been developed to understand the mechanisms involved in pain response, as well as to discover novel pharmacological and non-pharmacological anti-pain therapies. Due to the genetic tractability, similar physiology, low cost, and rich behavioral repertoire, the zebrafish (Danio rerio) has been considered a powerful aquatic model for modeling pain responses. Here, we summarize the molecular machinery of zebrafish to recognize painful stimuli, as well as emphasize how zebrafish-based pain models have been successfully used to understand specific molecular, physiological, and behavioral changes following different algogens and/or noxious stimuli (e.g., acetic acid, formalin, histamine, Complete Freund's Adjuvant, cinnamaldehyde, allyl isothiocyanate, and fin clipping). We also discuss recent advances in zebrafish-based studies and outline the potential advantages and limitations of the existing models to examine the mechanisms underlying pain responses from an evolutionary and translational perspective. Finally, we outline how zebrafish models can represent emergent tools to explore pain behaviors and pain-related mood disorders, as well as to facilitate analgesic therapy screening in translational pain research.
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Affiliation(s)
- Fabiano V Costa
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria RS. Brazil
| | - Luiz V Rosa
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria RS. Brazil
| | - Vanessa A Quadros
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria RS. Brazil
| | - Murilo S de Abreu
- Bioscience Institute, University of Passo Fundo (UPF), Passo Fundo, RS. Brazil
| | - Adair R S Santos
- Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Trindade, Florianópolis, SC. Brazil
| | - Lynne U Sneddon
- University of Gothenburg, Department of Biological & Environmental Sciences, Box 461, SE-405 30 Gothenburg. Sweden
| | - Allan V Kalueff
- School of Pharmacy, Southwest University, Chongqing, China; Ural Federal University, Ekaterinburg. Russian Federation
| | - Denis B Rosemberg
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria RS. Brazil
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34
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Li J, Kong L, Huang H, Luan S, Jin R, Wu F. ASIC1a inhibits cell pyroptosis induced by acid-induced activation of rat hepatic stellate cells. FEBS Open Bio 2020; 10:1044-1055. [PMID: 32237041 PMCID: PMC7262943 DOI: 10.1002/2211-5463.12850] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 03/11/2020] [Accepted: 03/25/2020] [Indexed: 12/19/2022] Open
Abstract
The activation of hepatic stellate cells (HSCs) is associated with liver fibrosis, the pathological feature of most forms of chronic hepatic damage, and is accompanied by abnormal deposition of the extracellular matrix (ECM). During the pathological process, acid-sensing ion channel 1a (ASIC1a), which is responsible for Ca2+ transportation, is involved in the activation of HSCs. It has previously been identified that ASIC1a is related to pyroptosis in articular chondrocytes. However, it remains unclear whether ASIC1a restrains pyroptosis during liver fibrosis. Here, we determined that the levels of pyroptosis-associated speck-like protein, gasdermin D, caspase-1, nucleotide-binding oligomerization domain (NOD)-like receptor 3, and apoptosis-associated speck-like protein (ASC) decreased, while the level of α-smooth muscle actin and collagen-I increased upon introduction of ASIC1a into an acid-induced model. Inhibition or silencing of ASIC1a and the use of Ca2+ -free medium were able to promote the pyroptosis of activated HSCs, which reduced their deposition. In summary, our study indicates that ASIC1a inhibits pyroptosis of HSCs and that inhibition of ASIC1a may be able to promote pyroptosis to relieve liver fibrosis.
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Affiliation(s)
- Jun Li
- School of PharmacyAnhui Medical UniversityHefeiChina
| | - Lingjin Kong
- School of PharmacyAnhui Medical UniversityHefeiChina
| | - Huiping Huang
- School of PharmacyAnhui Medical UniversityHefeiChina
| | - Shaohua Luan
- School of PharmacyAnhui Medical UniversityHefeiChina
| | - Rui Jin
- School of PharmacyAnhui Medical UniversityHefeiChina
| | - Fanrong Wu
- School of PharmacyAnhui Medical UniversityHefeiChina
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Khataei T, Harding AMS, Janahmadi M, El-Geneidy M, Agha-Alinejad H, Rajabi H, Snyder PM, Sluka KA, Benson CJ. ASICs are required for immediate exercise-induced muscle pain and are downregulated in sensory neurons by exercise training. J Appl Physiol (1985) 2020; 129:17-26. [PMID: 32463731 DOI: 10.1152/japplphysiol.00033.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Exercise training is an effective therapy for many pain-related conditions, and trained athletes have lower pain perception compared with unconditioned people. Some painful conditions, including strenuous exercise, are associated with elevated levels of protons, metabolites, and inflammatory factors, which may activate receptors and/or ion channels, including acid-sensing ion channels (ASICs), on nociceptive sensory neurons. We hypothesized that ASICs are required for immediate exercise-induced muscle pain (IEIP) and that exercise training diminishes IEIP by modulating ASICs within muscle afferents. We found high-intensity interval training (HIIT) reduced IEIP in C57BL/6 mice and diminished ASIC mRNA levels in lumber dorsal root ganglia, and this downregulation of ASICs correlated with improved exercise capacity. Additionally, we found that ASIC3 -/- mice did not develop IEIP; however, the exercise capacity of ASIC3 -/- was similar to wild-type mice. These results suggest that ASICs are required for IEIP and that diminishment of IEIP after exercise training correlates with downregulation of ASICs in sensory neurons.NEW & NOTEWORTHY Exercise performance can be limited by the sensations of muscle fatigue and pain transmitted by muscle afferents. It has been proposed that exercise training abrogates these negative feedback signals. We found that acid-sensing ion channels (ASICs) are required for immediate exercise-induced muscle pain (IEIP). Moreover, exercise training prevented IEIP and was correlated with downregulation of ASICs in sensory neurons.
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Affiliation(s)
- Tahsin Khataei
- Department of Exercise Physiology, Tarbiat Modares University, Tehran, Iran.,Department of Internal Medicine, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa.,Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa
| | - Anne Marie S Harding
- Department of Internal Medicine, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa.,Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa
| | - Mahyar Janahmadi
- Department of Physiology and Neuroscience Research Center, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maram El-Geneidy
- Department of Internal Medicine, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa.,Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa
| | | | - Hamid Rajabi
- Department of Exercise Physiology, Kharazmi University, Tehran, Iran
| | - Peter M Snyder
- Department of Internal Medicine, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa.,Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa
| | - Kathleen A Sluka
- Department of Physical Therapy and Rehabilitation Science, The University of Iowa, Iowa City, Iowa.,Neuroscience Institute, The University of Iowa, Iowa City, Iowa
| | - Christopher J Benson
- Department of Internal Medicine, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa.,Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa.,Department of Pharmacology, University of Iowa, Roy J. and Lucile A. Carver College of Medicine, Iowa City, Iowa
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36
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Rook ML, Musgaard M, MacLean DM. Coupling structure with function in acid-sensing ion channels: challenges in pursuit of proton sensors. J Physiol 2020; 599:417-430. [PMID: 32306405 DOI: 10.1113/jp278707] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/27/2020] [Indexed: 12/25/2022] Open
Abstract
Acid-sensing ion channels (ASICs) are a class of trimeric cation-selective ion channels activated by changes in pH within the physiological range. They are widely expressed in the central and peripheral nervous systems where they participate in a range of physiological and pathophysiological situations such as learning and memory, pain sensation, fear and anxiety, substance abuse and cell death. ASICs are localized to cell bodies and dendrites, including the postsynaptic density, and within the last 5 years several examples of proton-evoked ASIC excitatory postsynaptic currents have emerged. Thus, ASICs have become bona fide neurotransmitter-gated ion channels, activated by the smallest neurotransmitter possible: protons. Here we review how protons are thought to drive the conformational changes associated with ASIC activation and desensitization. In particular, we weigh the evidence for and against the so-called 'acidic pocket' being a vital proton sensor and discuss the emerging role of the β11-12 linker as a desensitization switch or 'molecular clutch'. We also examine how proton-induced conformational changes pose unique challenges to classical molecular dynamics simulations, as well as some possible solutions. Given the emergence of new methodologies and structures, the coming years will probably see many advances in the study of acid-sensing ion channels.
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Affiliation(s)
- Matthew L Rook
- Graduate Program in Cellular and Molecular Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY, 14642, USA
| | - Maria Musgaard
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, 75 Laurier Ave E, Ottawa, ON, K1N 6N5, Canada
| | - David M MacLean
- Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY, 14642, USA
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37
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Kim JS, Ducrocq GP, Kaufman MP. Functional knockout of ASIC3 attenuates the exercise pressor reflex in decerebrated rats with ligated femoral arteries. Am J Physiol Heart Circ Physiol 2020; 318:H1316-H1324. [PMID: 32302492 PMCID: PMC7346538 DOI: 10.1152/ajpheart.00137.2020] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/23/2020] [Accepted: 04/12/2020] [Indexed: 11/22/2022]
Abstract
The exercise pressor reflex arises from contracting muscle and is manifested by increases in arterial pressure, heart rate, and cardiac contractility. In patients with peripheral artery disease, the exercise pressor reflex is exaggerated. This effect is believed to be caused by a metabolite whose concentration is increased when the working muscles are inadequately perfused. Previous work in rats with simulated peripheral artery disease has shown that pharmacological blockade of acid-sensing ion channel 3 (ASIC3), which is found on group III and IV afferents, prevented the exaggeration of the exercise pressor reflex. Blockade of ASIC3, however, may have off-target effects that preclude a conclusion that ASIC3 plays a role in evoking the reflex in rats with simulated peripheral artery disease. In the present experiments performed in decerebrated rats with simulated peripheral artery disease, we compared the exercise pressor reflex in rats with a functional knockout of the ASIC3 (KO) with the reflex in their wild-type counterparts (WT). We found that the exercise pressor reflex in ASIC3 KO rats was significantly lower than the exercise pressor reflex in their WT counterparts (P < 0.05). ASIC 3 KO rats demonstrated lower pressor responses to intra-arterial injection of diprotonated phosphate (86 mM; pH 6.0), lactic acid (12 mM; pH 2.85), and capsaicin (0.2 μg; pH 7.2) (P < 0.05). In contrast, both ligated WT and ASIC3 KO rats displayed similar pressor responses to tendon stretch (P > 0.05). We conclude that ASIC3 play an important role in evoking the exaggerated exercise pressor reflex in rats with peripheral artery disease.NEW & NOTEWORTHY We used a genetic approach to test the hypothesis that the magnitude of the exercise pressor reflex evoked in ligated ASIC3 KO rats was significantly lower than the magnitude of the exercise pressor reflex evoked in their ligated wild-type (WT) counterparts. The pressor response to contraction in ligated ASIC3 KO rats was significantly smaller than was the pressor response to contraction in ligated WT rats.
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Affiliation(s)
- Joyce S Kim
- Heart and Vascular Institute and Department of Medicine, Penn State College of Medicine, Hershey, Pennsylvania
| | - Guillaume P Ducrocq
- Heart and Vascular Institute and Department of Medicine, Penn State College of Medicine, Hershey, Pennsylvania
| | - Marc P Kaufman
- Heart and Vascular Institute and Department of Medicine, Penn State College of Medicine, Hershey, Pennsylvania
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38
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Carattino MD, Montalbetti N. Acid-sensing ion channels in sensory signaling. Am J Physiol Renal Physiol 2020; 318:F531-F543. [PMID: 31984789 DOI: 10.1152/ajprenal.00546.2019] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Acid-sensing ion channels (ASICs) are cation-permeable channels that in the periphery are primarily expressed in sensory neurons that innervate tissues and organs. Soon after the cloning of the ASIC subunits, almost 20 yr ago, investigators began to use genetically modified mice to assess the role of these channels in physiological processes. These studies provide critical insights about the participation of ASICs in sensory processes, including mechanotransduction, chemoreception, and nociception. Here, we provide an extensive assessment of these findings and discuss the current gaps in knowledge with regard to the functions of ASICs in the peripheral nervous system.
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Affiliation(s)
- Marcelo D Carattino
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Nicolas Montalbetti
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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39
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Hossain MZ, Ando H, Unno S, Nakamoto T, Kitagawa J. Functional involvement of acid-sensing ion channel 3 in the swallowing reflex in rats. Neurogastroenterol Motil 2020; 32:e13728. [PMID: 31565832 DOI: 10.1111/nmo.13728] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 08/20/2019] [Accepted: 09/05/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Difficulty swallowing represents a major health problem. Swallowing function is improved by incorporating weak acids in suspensions/food boluses, implicating acid-sensing ion channels (ASICs) in the swallowing reflex. However, the functional involvement of ASICs in the swallowing reflex has not been fully elucidated. METHODS We localized ASIC3s in swallowing-related regions innervated by the superior laryngeal nerves (SLNs) and those in the nodose-petrosal-jugular ganglionic complex (NPJc) and examined their functional involvement in evoking the swallowing reflex in rats. KEY RESULTS We localized ASIC3s on epithelial cells and nerve fibers in swallowing-related regions innervated by the SLNs. In the NPJc, around half of the SLN-afferent neurons expressed ASIC3. Two-thirds of ASIC3s were localized on unmyelinated neurons in the nodose and petrosal ganglia. In the jugular ganglia, they were equally distributed on unmyelinated and myelinated neurons. Topical application of a synthetic non-proton ASIC3 activator, 2-guanidine-4-methylquinazoline (GMQ), and its natural endogenous ligand agmatine (a metabolite of the amino acid arginine) in swallowing-related regions evoked a considerable number of swallowing reflexes. Increasing the concentration of GMQ and agmatine up to a certain concentration increased the number of evoked reflexes and shortened the interval between the evoked reflexes. Agmatine was less potent than GMQ in its ability to evoke swallowing reflexes. Prior topical application of an ASIC3 antagonist significantly attenuated the number of GMQ- and agmatine-evoked swallowing reflexes. CONCLUSIONS & INFERENCES Acid-sensing ion channel 3s localized on nerves and epithelial cells in swallowing-related regions are functional in evoking the swallowing reflex and activation of these channels via a pharmacological agonist appears to improve swallowing behavior.
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Affiliation(s)
- Mohammad Zakir Hossain
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, Shiojiri, Japan
| | - Hiroshi Ando
- Department of Biology, Institute for Oral Science, Matsumoto Dental University, Shiojiri, Japan
| | - Shumpei Unno
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, Shiojiri, Japan
| | - Tetsuji Nakamoto
- Division of Oral Pathogenesis and Disease Control, Department of Oral Implantology, Asahi University School of Dentistry, Mizuho, Japan
| | - Junichi Kitagawa
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, Shiojiri, Japan
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40
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Mango D, Nisticò R. Role of ASIC1a in Normal and Pathological Synaptic Plasticity. Rev Physiol Biochem Pharmacol 2020; 177:83-100. [PMID: 32789788 DOI: 10.1007/112_2020_45] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Acid-sensing ion channels (ASICs), members of the degenerin/epithelial Na+ channel superfamily, are broadly distributed in the mammalian nervous system where they play important roles in a variety of physiological processes, including neurotransmission and memory-related behaviors. In the last few years, we and others have investigated the role of ASIC1a in different forms of synaptic plasticity especially in the CA1 area of the hippocampus. This review summarizes the latest research linking ASIC1a to synaptic function either in physiological or pathological conditions. A better understanding of how these channels are regulated in brain circuitries relevant to synaptic plasticity and memory may offer novel targets for pharmacological intervention in neuropsychiatric and neurological disorders.
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Affiliation(s)
- Dalila Mango
- Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, Rome, Italy.
| | - Robert Nisticò
- Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, Rome, Italy
- School of Pharmacy, University of Rome Tor Vergata, Rome, Italy
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41
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Ducrocq GP, Kim JS, Estrada JA, Kaufman MP. ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex in rats. Am J Physiol Heart Circ Physiol 2020; 318:H78-H89. [PMID: 31675256 PMCID: PMC6985806 DOI: 10.1152/ajpheart.00565.2019] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/23/2019] [Accepted: 10/28/2019] [Indexed: 11/22/2022]
Abstract
The role of the acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex is unknown, despite the fact that ASIC1a is opened by decreases in pH in the physiological range. This fact prompted us to test the hypothesis that ASIC1a plays an important role in evoking the exercise pressor reflex in decerebrated rats with freely perfused hindlimb muscles. To test this hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles on the reflex pressor responses to four maneuvers, namely 1) static contraction of the triceps surae muscles (i.e., the exercise pressor reflex), 2) calcaneal tendon stretch, 3) intra-arterial injection of lactic acid, and 4) intra-arterial injection of diprotonated phosphate. We found that the 2 ASIC1a blockers, psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 μg/kg), decreased the pressor responses to static contraction as well as the peak pressor responses to injection of lactic acid and diprotonated phosphate. In contrast, neither ASIC1a blocker had any effect on the pressor responses to tendon stretch. Importantly, we found that ASIC1a blockade significantly decreased the pressor response to static contraction after a latency of at least 8 s. Our results support the hypothesis that ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex.NEW & NOTEWORTHY The role played by acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex remains unknown. In decerebrated rats with freely perfused femoral arteries, blocking ASIC1a with psalmotoxin-1 or mambalgin-1 significantly attenuated the pressor response to static contraction, lactic acid, and diprotonated phosphate injection but had no effect on the pressor response to stretch. We conclude that ASIC1a plays a key role in evoking the exercise pressor reflex by responding to contraction-induced metabolites, such as protons.
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Affiliation(s)
- Guillaume P Ducrocq
- Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania
| | - Joyce S Kim
- Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania
| | - Juan A Estrada
- Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania
| | - Marc P Kaufman
- Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania
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42
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ASIC1a promotes synovial invasion of rheumatoid arthritis via Ca 2+/Rac1 pathway. Int Immunopharmacol 2019; 79:106089. [PMID: 31865241 DOI: 10.1016/j.intimp.2019.106089] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/26/2019] [Accepted: 11/26/2019] [Indexed: 01/14/2023]
Abstract
Acid-sensitive ion channels (ASICs) as Ca2+ and Na+ cation channels are activated by changing in extracellular pH, which expressed in various diseases and participated in underlying pathogenesis. ASIC1a is involved in migration and invasion of various tumor cells. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) located at the edge of the synovium were identified as key players in the pathophysiological process of rheumatoid arthritis and reported to have many similar properties to tumor cells. Here, we investigated the roles of ASIC1a in synovial invasion in vivo and the migration and invasion of RA-FLSs in vitro. Our results showed ASIC1a highly expressed in RA synovial tissues and RA-FLSs. Inhibition of ASIC1a by PCTX-1 reduces synovial invasion and the expressions of MMP2, MMP9, p-FAK to protect articular cartilage in AA rats. Moreover, the acidity-promoted invasion and migration as well as the expressions of MMP2, MMP9, p-FAK of RA-FLSs were down-regulated by ASIC1a-RNAi and PCTX-1 while they were increased by overexpression-ASIC1a. ASIC1a mediated Ca2+ influx and the activation of Ras-related C3 botulinum toxin substrate 1(Rac1), which was decreased by the intracellular calcium chelating agent BAPTA-AM. Meanwhile, the migration and invasion as well as the expressions of MMP2, MMP9, p-FAK of RA-FLSs were decreased by Rac1 specific blocker NSC23766. In conclusion, this study indicated that ASIC1a may be a master regulator of synovial invasion via Ca2+/Rac1 pathway.
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43
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Chang CT, Fong SW, Lee CH, Chuang YC, Lin SH, Chen CC. Involvement of Acid-Sensing Ion Channel 1b in the Development of Acid-Induced Chronic Muscle Pain. Front Neurosci 2019; 13:1247. [PMID: 31824248 PMCID: PMC6882745 DOI: 10.3389/fnins.2019.01247] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 11/05/2019] [Indexed: 12/26/2022] Open
Abstract
Acid-sensing ion channels (ASICs) are important acid sensors involved in neural modulation in the central nervous system and pain-associated tissue acidosis in the peripheral system. Among ASIC subtypes, ASIC1b is the most selectively expressed in peripheral sensory neurons. However, the role of ASIC1b is still elusive in terms of its functions and expression profile. In this study, we probed the role of ASIC1b in acid-induced muscle pain in Asic1b-knockout (Asic1b–/–) and Asic1b-Cre transgenic (Asic1bCre) mice. We tested the effect of ASIC1b knockout in a mouse model of fibromyalgia induced by dual intramuscular acid injections. In this model, a unilateral acid injection to the gastrocnemius muscle induced transient bilateral hyperalgesia in wild-type (Asic1b+/+) but not Asic1b–/– mice; a second acid injection, spaced 1 or 5 days apart, to the same muscle induced chronic hyperalgesia lasting for 4 weeks in Asic1b+/+ mice, but the duration of hyperalgesia was significantly shortened in Asic1b–/– mice. Mambalgin-1, an ASIC1b-containing channel inhibitor that was mixed with acid saline at the first injection, dose-dependently blocked the acid-induced transient and chronic hyperalgesia in Asic1b+/+ mice. In contrast, psalmotoxin 1 (PcTx1), an ASIC1a-selective antagonist, had no effect on acid-induced transient or chronic hyperalgesia. We used whole-cell patch clamp recording to study the properties of acid-induced currents in ASIC1b-expressing dorsal root ganglia (DRG) neurons from Asic1bCre-TdTomato reporter mice. Medium- to large-sized ASIC1b-expressing DRG neurons mainly exhibited an amiloride-sensitive ASIC-like biphasic current (IASIC) in response to acid stimulation, whereas small- to medium-sized ASIC1b-expressing DRG neurons predominantly exhibited an amiloride-insensitive sustained current. Specifically, mambalgin-1 selectively inhibited the IASIC in most ASIC1b-expressing DRG neurons. However, PcTx1 or APETx2 (an ASIC3-selective antagonist) had only a mild inhibitory effect on IASIC in about half of the ASIC1b-expressing DRG neurons. In situ hybridization revealed that ASIC1b-positive DRG neurons co-expressed highly with ASIC1a and ASIC2a mRNA and partially with ASIC3 and ASIC2b. Thus, ASIC1b might form a wide variety of heteromeric channels. ASIC1b-containing heteromeric channels might be promising targets for the therapeutic treatment of acid-induced chronic muscle pain.
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Affiliation(s)
- Chu-Ting Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Sitt Wai Fong
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Academia Sinica, Taipei, Taiwan
| | - Cheng-Han Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yu-Chia Chuang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Shing-Hong Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Department of Neurobiology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
| | - Chih-Cheng Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Academia Sinica, Taipei, Taiwan
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44
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Pattison LA, Callejo G, St John Smith E. Evolution of acid nociception: ion channels and receptors for detecting acid. Philos Trans R Soc Lond B Biol Sci 2019; 374:20190291. [PMID: 31544616 PMCID: PMC6790391 DOI: 10.1098/rstb.2019.0291] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2019] [Indexed: 12/13/2022] Open
Abstract
Nociceptors, i.e. sensory neurons tuned to detect noxious stimuli, are found in numerous phyla of the Animalia kingdom and are often polymodal, responding to a variety of stimuli, e.g. heat, cold, pressure and chemicals, such as acid. Owing to the ability of protons to have a profound effect on ionic homeostasis and damage macromolecular structures, it is no wonder that the ability to detect acid is conserved across many species. To detect changes in pH, nociceptors are equipped with an assortment of different acid sensors, some of which can detect mild changes in pH, such as the acid-sensing ion channels, proton-sensing G protein-coupled receptors and several two-pore potassium channels, whereas others, such as the transient receptor potential vanilloid 1 ion channel, require larger shifts in pH. This review will discuss the evolution of acid sensation and the different mechanisms by which nociceptors can detect acid. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
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Affiliation(s)
| | | | - Ewan St John Smith
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK
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45
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Cakir Z, Yildirim C, Buran I, Önalan EE, Bal R. Acid-sensing ion channels (ASICs) influence excitability of stellate neurons in the mouse cochlear nucleus. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2019; 205:769-781. [PMID: 31451914 DOI: 10.1007/s00359-019-01365-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 08/08/2019] [Accepted: 08/13/2019] [Indexed: 02/06/2023]
Abstract
Acid-sensing ion channels (ASICs) are voltage-independent and proton-gated channels. In this study, we aimed to test the hypothesis whether ASICs might be involved in modifying the excitability of stellate cells in the cochlear nucleus (CN). We determined gene expressions of ASIC1, ASIC2 and ASIC3 in the CN of BALB/mice. ASIC currents in stellate cells were characterized by using whole-cell patch-clamp technique. In the voltage-clamp experiments, inward currents were recorded upon application of 2-[N-Morpholino ethanesulfonic acid]-normal artificial cerebrospinal fluid (MES-aCSF), whose pH 50 was 5.84. Amiloride inhibited the acid-induced currents in a dose-dependent manner. Inhibition of the ASIC currents by extracellular Ca2+ and Pb2+ (10 μM) was significant evidence for the existence of homomeric ASIC1a subunits. ASIC currents were increased by 20% upon extracellular application of Zn2+ (300 μM) (p < 0.05, n = 13). In current-clamp experiments, application of MES-aCSF resulted in the depolarization of stellate cells. The results show that the ASIC currents in stellate cells of the cochlear nucleus are carried largely by the ASIC1a and ASIC2a channels. ASIC channels affect the excitability of the stellate cells and therefore they appear to have a role in the processing of auditory information.
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Affiliation(s)
- Ziya Cakir
- Department of Physiology, Faculty of Medicine, Tokat Gaziosmanpasa University, 60250, Tokat, Turkey
| | - Caner Yildirim
- Department of Physiology, Faculty of Medicine, Kafkas University, 36100, Kars, Turkey
| | - Ilay Buran
- Department of Medical Biology, Faculty of Medicine, Firat University, 23100, Elazig, Turkey
| | - Ebru Etem Önalan
- Department of Medical Biology, Faculty of Medicine, Firat University, 23100, Elazig, Turkey
| | - Ramazan Bal
- Department of Physiology, Faculty of Medicine, Gaziantep University, 27310, Gaziantep, Turkey.
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46
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Detweiler ND, Herbert LM, Garcia SM, Yan S, Vigil KG, Sheak JR, Resta TC, Walker BR, Jernigan NL. Loss of acid-sensing ion channel 2 enhances pulmonary vascular resistance and hypoxic pulmonary hypertension. J Appl Physiol (1985) 2019; 127:393-407. [PMID: 31169471 PMCID: PMC6732443 DOI: 10.1152/japplphysiol.00894.2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 05/03/2019] [Accepted: 05/29/2019] [Indexed: 11/22/2022] Open
Abstract
Acid-sensing ion channels (ASICs) are voltage-insensitive cation channels that contribute to cellular excitability. We previously reported that ASIC1 in pulmonary artery smooth muscle cells (PASMC) contribute to pulmonary vasoreactivity and vascular remodeling during the development of chronic hypoxia (CH)-induced pulmonary hypertension. However, the roles of ASIC2 and ASIC3 in regulation of pulmonary vasoreactivity and the development of CH-induced pulmonary hypertension are unknown. We tested the hypothesis that ASIC2 and ASIC3 contribute to increased pulmonary vasoreactivity and development of CH-induced pulmonary hypertension using ASIC2- and ASIC3-knockout (-/-) mice. In contrast to this hypothesis, we found that ASIC2-/- mice exhibit enhanced CH-induced pulmonary hypertension compared with WT and ASIC3-/- mice. This response was not associated with a change in ventilatory sensitivity or systemic cardiovascular function but was instead associated with direct changes in pulmonary vascular reactivity and pulmonary arterial morphology in ASIC2-/- mice. This increase in reactivity correlated with enhanced pulmonary arterial basal tone, elevated basal PASMC [Ca2+] and store-operated calcium entry (SOCE) in PASMC from ASIC2-/- mice. This increase in PASMC [Ca2+] and vasoreactivity was dependent on ASIC1-mediated Ca2+ influx but was not contingent upon an increase in ASIC1 mRNA or protein expression in PASMC from ASIC2-/- mice. Together, the results from this study demonstrate an important role for ASIC2 to regulate pulmonary vascular reactivity and for ASIC2 to modulate the development of CH-induced pulmonary hypertension. These data further suggest that loss of ASIC2 enhances the contribution of ASIC1 to overall pulmonary vascular reactivity.NEW & NOTEWORTHY This study demonstrates that loss of ASIC2 leads to increased baseline pulmonary vascular resistance, enhanced responses to a variety of vasoconstrictor stimuli, and greater development of hypoxic pulmonary hypertension. Furthermore, these results suggest that loss of ASIC2 enhances the contribution of ASIC1 to pulmonary vascular reactivity.
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Affiliation(s)
- Neil D Detweiler
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center Albuquerque, New Mexico
| | - Lindsay M Herbert
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center Albuquerque, New Mexico
| | - Selina M Garcia
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center Albuquerque, New Mexico
| | - Simin Yan
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center Albuquerque, New Mexico
| | - Kenneth G Vigil
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center Albuquerque, New Mexico
| | - Joshua R Sheak
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center Albuquerque, New Mexico
| | - Thomas C Resta
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center Albuquerque, New Mexico
| | - Benjimen R Walker
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center Albuquerque, New Mexico
| | - Nikki L Jernigan
- Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center Albuquerque, New Mexico
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Gao WF, Xu YY, Ge JF, Chen FH. Inhibition of acid‑sensing ion channel 1a attenuates acid‑induced activation of autophagy via a calcium signaling pathway in articular chondrocytes. Int J Mol Med 2019; 43:1778-1788. [PMID: 30720055 PMCID: PMC6414154 DOI: 10.3892/ijmm.2019.4085] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 01/30/2019] [Indexed: 12/16/2022] Open
Abstract
Acid-sensing ion channel 1a (ASIC1a), member of the degenerin/epithelial sodium channel protein superfamily, serves a critical role in various physiological and pathological processes. The aim of the present study was to examine the role of ASIC1a in the autophagy of rat articular chondrocytes. Autophagy was induced by acidic stimulation in rat articular chondrocytes and the extent of autophagy was evaluated via the expression levels of microtubule-associated protein 1 light chain 3II, Beclin1 and uncoordinated-51 like kinase1. Suppression of ASIC1a was achieved using small interfering RNA technology and/or inhibitor psalmotoxin-1. The expression levels of autophagy markers were measured by western blot analysis and reverse transcription-quantitative polymerase chain reaction methods. Intracellular calcium ([Ca2+]i) was analyzed using a Ca2+-imaging method. Additionally, protein expression levels of the Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)/5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway were measured by western blot analysis. The results showed that autophagy was increased in a pH-and time-dependent manner with exposure to an acidic environment. In addition, silencing ASIC1a significantly decreased the expression levels of autophagy makers, accompanied by abrogation of the acid-induced [Ca2+]i increase. Furthermore, silencing of ASIC1a downregulated the levels of CaMKKβ/β-actin and phosphorylated (p-) AMPK/AMPK, and upregulated the levels of p-mTOR/mTOR. These results indicated that ASIC1a is a potent regulator of autophagy in chondrocytes, which may be associated with decreased Ca2+ influx and the CaMKKβ/AMPK/mTOR pathway.
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Affiliation(s)
- Wen-Fan Gao
- Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, P.R. China
| | - Ya-Yun Xu
- Department of Pharmacy, Anhui Mental Health Center, Hefei, Anhui 230000, P.R. China
| | - Jin-Fang Ge
- School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Fei-Hu Chen
- School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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48
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Wan Y, Yu Y, Pan X, Mo X, Gong W, Liu X, Chen S. Inhibition on acid-sensing ion channels and analgesic activities of flavonoids isolated from dragon's blood resin. Phytother Res 2019; 33:718-727. [PMID: 30618119 DOI: 10.1002/ptr.6262] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 10/08/2018] [Accepted: 11/23/2018] [Indexed: 11/08/2022]
Abstract
Acid-sensing ion channel (ASIC) serves important roles in the transmission of nociceptive information. To confirm the analgesic mechanism of dragon's blood resin, patch-clamp technique, in vivo animal experiments, and immunohistochemical staining were used to observe the effects of the three flavonoids (loureirin B, cochinchinemin A, and cochinchinemin B) isolated from dragon's blood resin on ASIC. Results showed that the three flavonoids exerted various inhibitory effects on ASIC currents in rat dorsal root ganglion (DRG) neurons. The combination of the three flavonoids with total concentration of 6.5 μM could decrease (53.8 ± 4.3%) of the peak amplitude and (45.8 ± 4.5%) of the sustained portion of ASIC currents. The combination of the three flavonoids was fully efficacious on complete Freud's adjuvant (CFA)-induced inflammatory thermal hyperalgesia at a dose of 6.5 mM similar with amiloride at 10 mM. The analgesic effects of the combination could be weakened by an ASIC activator 2-guanidine-4-methylquinazoline. CFA-induced hyperalgesia was accompanied by c-Fos up-regulation in DRG neurons, and the combination rescued thermal hyperalgesia through down-regulation of c-Fos and ASIC3 expression in CFA-induced inflammation. These collective results suggested that the flavonoids isolated from dragon's blood resin could be considered as the chemical compounds that exert analgesic effects on inflammatory thermal pain due to action on ASIC.
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Affiliation(s)
- Ying Wan
- College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, China.,Key Laboratory of Cognitive Science of State Ethnic Affairs Commission, Wuhan, China.,Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, Wuhan, China
| | - Yi Yu
- College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, China.,Key Laboratory of Cognitive Science of State Ethnic Affairs Commission, Wuhan, China.,Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, Wuhan, China
| | - Xinxin Pan
- College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, China.,Key Laboratory of Cognitive Science of State Ethnic Affairs Commission, Wuhan, China.,Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, Wuhan, China
| | - Xiaoqiang Mo
- Basic Medical College, Youjiang Medical University for Nationalities, Baise, China
| | - Weifan Gong
- College of Pharmacy, South-Central University for Nationalities, Wuhan, China
| | - Xiangming Liu
- School of Nursing, Gongqing Institute of Science and Technology, Jiujiang, China
| | - Su Chen
- College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, China.,Key Laboratory of Cognitive Science of State Ethnic Affairs Commission, Wuhan, China.,Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, Wuhan, China
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Dibas J, Al-Saad H, Dibas A. Basics on the use of acid-sensing ion channels' inhibitors as therapeutics. Neural Regen Res 2019; 14:395-398. [PMID: 30539804 PMCID: PMC6334597 DOI: 10.4103/1673-5374.245466] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Since the discovery of acid-sensing ion channels in 1997, their importance in the health of neurons and other non-neuronal cells has gained significant importance. Acid-sensing ion channels play important roles in mediating pain sensation during diseases such as stroke, inflammation, arthritis, cancer, and recently migraine. More interestingly, acid-sensing ion channels may explain the sex differences in pain between males and females. Also, the ability of acid-sensing ion channel blockers to exert neuroprotective effects in a number of neurodegenerative diseases has added a new dimension to their therapeutic value. The current failure rate of ~45% of new drugs (due to toxicity issues) and saving of up to 7 years in the life span of drug approval makes drug repurposing a high priority. If acid-sensing ion channels’ blockers undergo what is known as “drug repurposing”, there is a great potential to bring them as medications with known safety profiles to new patient populations. However, the route of administration remains a big challenge due to their poor penetration of the blood brain and retinal barriers. In this review, the promise of using acid-sensing ion channel blockers as neuroprotective drugs is discussed.
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Affiliation(s)
- Jamileh Dibas
- Faculty of Pharmacy, Applied University, Amman, Jordan
| | - Houssam Al-Saad
- North Texas Eye Research Institute, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX, USA
| | - Adnan Dibas
- North Texas Eye Research Institute, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX, USA
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Abstract
A large series of different ion channels have been identified and investigated as potential targets for new medicines for the treatment of a variety of human diseases, including pain. Among these channels, the voltage gated calcium channels (VGCC) are inhibited by drugs for the treatment of migraine, neuropathic pain or intractable pain. Transient receptor potential (TRP) channels are emerging as important pain transducers as they sense low pH media or oxidative stress and other mediators and are abundantly found at sites of inflammation or tissue injury. Low pH may also activate acid sensing ion channels (ASIC) and mechanical forces stimulate the PIEZO channels. While potent agonists of TRP channels due to their desensitizing action on pain transmission are used as topical applications, the potential of TRP antagonists as pain therapeutics remains an exciting field of investigation. The study of ASIC or PIEZO channels in pain signaling is in an early stage, whereas antagonism of the purinergic P2X3 channels has been reported to provide beneficial effects in chronic intractable cough. The present chapter covers these intriguing channels in great detail, highlighting their diverse mechanisms and broad potential for therapeutic utility.
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Affiliation(s)
- Francesco De Logu
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Pierangelo Geppetti
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
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