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Steib A, Rozmer K, Szőke É, Kun J, Farkas N, Feller D, Pongrácz J, Pohóczky K, Helyes Z. The TRPA1 cation channel is upregulated by cigarette smoke in mouse and human macrophages modulating lung inflammation. Sci Rep 2025; 15:10661. [PMID: 40148437 PMCID: PMC11950515 DOI: 10.1038/s41598-025-95662-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 03/24/2025] [Indexed: 03/29/2025] Open
Abstract
Cigarette smoke (CS) is a well-known source of several inflammatory, cytotoxic and genotoxic compounds that cause chronic lung diseases. The transient receptor potential ankyrin 1 (TRPA1), a smoking-responsive, non-selective cation channel, is expressed by both capsaicin-sensitive peptidergic sensory nerves and non-neuronal cells of the lung, but there are few and controversial data on its expression and function on macrophages. Here, we investigated TRPA1 mRNA and protein expression in mouse and human lung tissues and human 3D spheroids, with a particular focus on its expression and potential regulatory effects on pro- and anti-inflammatory macrophage functions in response to CS. TRPA1 was stably expressed in both human and mouse alveolar macrophages, being upregulated after CS exposure and its functional activity was demonstrated in mouse macrophage culture. Moreover, besides CS, the TRPA1 genotype itself affected the expression of M1- (Il-1β, Il-23) and M2-type (Il-10, Tgfβ) macrophage cytokines. Furthermore, CS extract increased TRPA1 mRNA in human lung spheroids showing more prominent expression in macrophage-containing 3D aggregates, while CS extract influenced an elevated TGFβ expression specifically in macrophage-containing spheroids. These results suggest the fine-tuning role of TRPA1 activation in CS-induced airway inflammation, particularly in macrophages, but further studies are needed to draw precise conclusions.
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Affiliation(s)
- Anita Steib
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- Hungarian Research Network, Chronic Pain Research Group (HUN-REN PTE), Pécs, Hungary
| | - Katalin Rozmer
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- Hungarian Research Network, Chronic Pain Research Group (HUN-REN PTE), Pécs, Hungary
- Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Pécs, Pécs, Hungary
| | - Éva Szőke
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- Hungarian Research Network, Chronic Pain Research Group (HUN-REN PTE), Pécs, Hungary
- National Laboratory for Drug Research and Development, Budapest, Hungary
| | - József Kun
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- National Laboratory for Drug Research and Development, Budapest, Hungary
- Hungarian Centre for Genomics and Bioinformatics, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Nelli Farkas
- Institute of Bioanalysis, Medical School, University of Pécs, Pécs, Hungary
| | - Diána Feller
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pécs, Pécs, Hungary
| | - Judit Pongrácz
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pécs, Pécs, Hungary
| | - Krisztina Pohóczky
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary.
- National Laboratory for Drug Research and Development, Budapest, Hungary.
- Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Pécs, Hungary.
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- Hungarian Research Network, Chronic Pain Research Group (HUN-REN PTE), Pécs, Hungary
- National Laboratory for Drug Research and Development, Budapest, Hungary
- PharmInVivo Ltd., Pécs, Hungary
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Zhu Y, Zhang T, Bai H, Li W, Wang S, Xu X, Yu L. PAR2 Participates in the Development of Cough Hypersensitivity in Guinea Pigs by Regulating TRPA1 Through PKC. Biomolecules 2025; 15:208. [PMID: 40001511 PMCID: PMC11853178 DOI: 10.3390/biom15020208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/28/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
OBJECTIVE This study was conducted to validate the involvement of the PAR2-PKC-TRPA1 pathway in cough hypersensitivity (CHS) development. METHODS Guinea pigs were divided into a blank control, a citric acid-induced enhanced cough model, and drug intervention groups. The effects of the drugs on capsaicin-induced cough responsiveness in a cough model were observed. The effects of individual and combined treatments (including PAR2 agonists, TRPA1 agonists, PAR2 antagonists, TRPA1 antagonists, PKC agonists, and PKC antagonists) on PAR2, phospho-PKC (pPKC), and TRPA1 expression in bronchial tissues and the vagus ganglion (jugular and nodose) in the cough model and control groups were assessed. Additionally, whole-cell patch-clamp recordings were conducted to evaluate the effects of the drugs on vagus ganglion neuron electrophysiological activity. RESULTS ① Both PAR2 antagonists and TRPA1 antagonists significantly reduced cough frequency in guinea pigs with a cough, and the PAR2 antagonist inhibited coughing induced by the TRPA1 agonist. ② Western blotting and multiplex immunohistochemistry (mIHC) indicated that PAR2, pPKCα, PKCα, and TRPA1 expression in bronchial and vagus ganglion tissues was elevated in the cough model compared with the control, with TRPA1 expression being regulated by PAR2 and PKC being involved in this regulatory process. ③ Whole-cell patch-clamp recordings demonstrated that TRPA1 agonists induced an inward current in nodose ganglion neurons, which was further amplified by PAR2 agonists; this amplification effect was blocked by PKC antagonist. Additionally, PAR2 antagonists inhibited the inward current induced by TRPA1 agonists. ④ At various concentrations, including the optimal antitussive concentration, PAR2 antagonists did not significantly affect pulse amplitude, arterial oxygen saturation, heart rate, body temperature, or respiratory rate in guinea pigs. CONCLUSION PAR2 regulates TRPA1 through PKC in cough syndrome (CHS) pathogenesis, making targeting PAR2 a safe and effective therapeutic strategy for CHS.
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Affiliation(s)
| | | | | | | | | | - Xianghuai Xu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China
| | - Li Yu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China
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Grach SL, Dudenkov DV, Pollack B, Fairweather D, Aakre CA, Munipalli B, Croghan IT, Mueller MR, Overgaard JD, Bruno KA, Collins NM, Li Z, Hurt RT, Tal MC, Ganesh R, Knight DTR. Overlapping conditions in Long COVID at a multisite academic center. Front Neurol 2024; 15:1482917. [PMID: 39524912 PMCID: PMC11543549 DOI: 10.3389/fneur.2024.1482917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024] Open
Abstract
Background Many patients experience persistent symptoms after COVID-19, a syndrome referred to as Long COVID (LC). The goal of this study was to identify novel new or worsening comorbidities self-reported in patients with LC. Methods Patients diagnosed with LC (n = 732) at the Mayo Long COVID Care Clinic in Rochester, Minnesota and Jacksonville, Florida were sent questionnaires to assess the development of new or worsening comorbidities following COVID-19 compared to patients with SARS-CoV-2 that did not develop LC (controls). Both groups were also asked questions screening for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), generalized joint hypermobility (GJH) and orthostatic intolerance. 247 people with LC (33.7%) and 40 controls (50%) responded to the surveys. Results In this study LC patients averaged 53 years of age and were predominantly White (95%) women (75%). The greatest prevalence of new or worsening comorbidities following SARS-CoV-2 infection in patients with LC vs. controls reported in this study were pain (94.4% vs. 0%, p < 0.001), neurological (92.4% vs. 15.4%, p < 0.001), sleep (82.8% vs. 5.3%, p < 0.001), skin (69.8% vs. 0%, p < 0.001), and genitourinary (60.6% vs. 25.0%, p = 0.029) issues. 58% of LC patients screened positive for ME/CFS vs. 0% of controls (p < 0.001), 27% positive for GJH compared to 10% of controls (p = 0.026), and a positive average score of 4.0 on orthostatic intolerance vs. 0 (p < 0.001). The majority of LC patients with ME/CFS were women (77%). Conclusion We found that comorbidities across 12 surveyed categories were increased in patients following SARS-CoV-2 infection. Our data also support the overlap of LC with ME/CFS, GJH, and orthostatic intolerance. We discuss the pathophysiologic, research, and clinical implications of identifying these conditions with LC.
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Affiliation(s)
- Stephanie L. Grach
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Daniel V. Dudenkov
- Department of General Internal Medicine, Mayo Clinic, Jacksonville, FL, United States
| | - Beth Pollack
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - DeLisa Fairweather
- Department of General Internal Medicine, Mayo Clinic, Jacksonville, FL, United States
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, United States
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN, United States
- Department of Immunology, Mayo Clinic, Jacksonville, FL, United States
| | - Chris A. Aakre
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Bala Munipalli
- Department of General Internal Medicine, Mayo Clinic, Jacksonville, FL, United States
| | - Ivana T. Croghan
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, United States
- Division of Quantitative Health Sciences, Rochester, MN, United States
| | - Michael R. Mueller
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Joshua D. Overgaard
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Katelyn A. Bruno
- Department of General Internal Medicine, Mayo Clinic, Jacksonville, FL, United States
- Department of Cardiovascular Medicine, University of Florida, Gainesville, FL, United States
| | - Nerissa M. Collins
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Zhuo Li
- Department of Biostatistics, Mayo Clinic, Jacksonville, FL, United States
| | - Ryan T. Hurt
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Michal C. Tal
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Ravindra Ganesh
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Dacre T. R. Knight
- Department of General Internal Medicine, Mayo Clinic, Jacksonville, FL, United States
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Tekulapally KR, Lee JY, Kim DS, Rahman MM, Park CK, Kim YH. Dual role of transient receptor potential ankyrin 1 in respiratory and gastrointestinal physiology: From molecular mechanisms to therapeutic targets. Front Physiol 2024; 15:1413902. [PMID: 39022308 PMCID: PMC11251976 DOI: 10.3389/fphys.2024.1413902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 06/10/2024] [Indexed: 07/20/2024] Open
Abstract
The transient receptor potential ankyrin 1 (TRPA1) channel plays a pivotal role in the respiratory and gastrointestinal tracts. Within the respiratory system, TRPA1 exhibits diverse distribution patterns across key cell types, including epithelial cells, sensory nerves, and immune cells. Its activation serves as a frontline sensor for inhaled irritants, triggering immediate protective responses, and influencing airway integrity. Furthermore, TRPA1 has been implicated in airway tissue injury, inflammation, and the transition of fibroblasts, thereby posing challenges in conditions, such as severe asthma and fibrosis. In sensory nerves, TRPA1 contributes to nociception, the cough reflex, and bronchoconstriction, highlighting its role in both immediate defense mechanisms and long-term respiratory reflex arcs. In immune cells, TRPA1 may modulate the release of pro-inflammatory mediators, shaping the overall inflammatory landscape. In the gastrointestinal tract, the dynamic expression of TRPA1 in enteric neurons, epithelial cells, and immune cells underscores its multifaceted involvement. It plays a crucial role in gut motility, visceral pain perception, and mucosal defense mechanisms. Dysregulation of TRPA1 in both tracts is associated with various disorders such as asthma, Chronic Obstructive Pulmonary Disease, Irritable Bowel Syndrome, and Inflammatory Bowel Disease. This review emphasizes the potential of TRPA1 as a therapeutic target and discusses the efficacy of TRPA1 antagonists in preclinical studies and their promise for addressing respiratory and gastrointestinal conditions. Understanding the intricate interactions and cross-talk of TRPA1 across different cell types provides insight into its versatile role in maintaining homeostasis in vital physiological systems, offering a foundation for targeted therapeutic interventions.
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Affiliation(s)
- Kavya Reddy Tekulapally
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Ji Yeon Lee
- Department of Anesthesiology and Pain Medicine, Gachon University, Gil Medical Center, Incheon, Republic of Korea
| | - Dong Seop Kim
- Department of Anesthesiology and Pain Medicine, Gachon University, Gil Medical Center, Incheon, Republic of Korea
| | - Md. Mahbubur Rahman
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Chul-Kyu Park
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Yong Ho Kim
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea
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Khoury P, Wechsler JB. Role of Mast Cells in Eosinophilic Gastrointestinal Diseases. Immunol Allergy Clin North Am 2024; 44:311-327. [PMID: 38575226 PMCID: PMC11220468 DOI: 10.1016/j.iac.2024.01.004] [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] [Indexed: 04/06/2024]
Abstract
Mast cells play a central role in the pathogenesis of eosinophilic gastrointestinal disorders (EGIDs), including eosinophilic esophagitis. Their interactions with immune and structural cells, involvement in tissue remodeling, and contribution to symptoms make them attractive targets for therapeutic intervention. More is being discovered regarding the intricate interplay of mast cells and eosinophils. Recent studies demonstrating that depletion of eosinophils is insufficient to improve symptoms of EGIDs have raised the question of whether other cells may play a role in symptomatology and pathogenesis of EGIDs.
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Affiliation(s)
- Paneez Khoury
- Human Eosinophil Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 12C103, Bethesda, MD 20892, USA.
| | - Joshua B Wechsler
- Simpson-Querrey 10-518, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E. Chicago Avenue, Box 65, Chicago, IL 60611, USA
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Yao Y, Liu ZJ, Zhang YK, Sun HJ. Mechanism and potential treatments for gastrointestinal dysfunction in patients with COVID-19. World J Gastroenterol 2022; 28:6811-6826. [PMID: 36632313 PMCID: PMC9827583 DOI: 10.3748/wjg.v28.i48.6811] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/01/2022] [Accepted: 12/07/2022] [Indexed: 12/26/2022] Open
Abstract
The global coronavirus disease 2019 (COVID-19) has become one of the biggest threats to the world since 2019. The respiratory and gastrointestinal tracts are the main targets for severe acute respiratory syndrome coronavirus 2 infection for they highly express angiotensin-converting enzyme-2 and transmembrane protease serine 2. In patients suffering from COVID-19, gastrointestinal symptoms have ranged from 12% to 61%. Anorexia, nausea and/or vomiting, diarrhea, and abdominal pain are considered to be the main gastrointestinal symptoms of COVID-19. It has been reported that the direct damage of intestinal mucosal epithelial cells, malnutrition, and intestinal flora disorders are involved in COVID-19. However, the underlying mechanisms remain unclear. Thus, in this study, we reviewed and discussed the correlated mechanisms that cause gastrointestinal symptoms in order to help to develop the treatment strategy and build an appropriate guideline for medical workers.
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Affiliation(s)
- Yang Yao
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, College of Basic Medical, Chongqing 404120, China
- Department of Clinical Pharmacology, College of Pharmacy, Dalian 116044, Liaoning Province, China
- Ministry of Public Infrastructure, Chongqing Three Gorges Medical College, Chongqing 404120, China
| | - Zhu-Jun Liu
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, College of Basic Medical, Chongqing 404120, China
- Department of Basic Medicine, Chongqing Three Gorges Medical College, Chongqing 404120, China
- Department of Business Administration, Metropolitan College of Science and Technology, Chongqing 404120, China
| | - Yu-Kun Zhang
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, College of Basic Medical, Chongqing 404120, China
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, Peking University, Beijing 100191, China
| | - Hui-Jun Sun
- Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area, College of Basic Medical, Chongqing 404120, China
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning Province, China
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Abstract
PURPOSE OF REVIEW This review will present what is known from recent research on the involvement of mast cells in eosinophilic esophagitis and identify questions requiring further investigation. RECENT FINDINGS In the adults and children with eosinophilic esophagitis, there is increasing evidence that mastocytosis can persist, despite resolution of eosinophilia and is associated with persistent mucosal abnormalities and symptoms. Despite, treatment mast cells have an activated transcriptome. Mast cells likely contribute to epithelial barrier dysfunction, smooth muscle hypertrophy and contraction, and subepithelial fibrosis. It remains unclear whether targeting MCs alone has therapeutic efficacy to improve tissue damage. SUMMARY Mast cells appear to play a key role in eosinophilic esophagitis and serve as a biomarker of mucosal healing in conjunction with eosinophils. Excessive mast cell activation likely contributes to tissue damage in eosinophilic esophagitis and need to be considered as a target of therapy along with eosinophils.
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Boudaka A, Tominaga M. Physiological and Pathological Significance of Esophageal TRP Channels: Special Focus on TRPV4 in Esophageal Epithelial Cells. Int J Mol Sci 2022; 23:ijms23094550. [PMID: 35562940 PMCID: PMC9099744 DOI: 10.3390/ijms23094550] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/16/2022] [Accepted: 04/19/2022] [Indexed: 12/10/2022] Open
Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel that is broadly expressed in different human tissues, including the digestive system, where it acts as a molecular sensor and a transducer that regulates a variety of functional activities. Despite the extensive research to determine the role of this channel in the physiology and pathophysiology of different organs, the unique morphological and functional features of TRPV4 in the esophagus remain largely unknown. Ten years ago, TRPV4 was shown to be highly expressed in esophageal epithelial cells where its activation induces Ca2+-dependent ATP release, which, in turn, mediates several functions, ranging from mechanosensation to wound healing. This review summarizes the research progress on TRPV4, and focuses on the functional expression of TRPV4 in esophageal epithelium and its possible role in different esophageal diseases that would support TRPV4 as a candidate target for future therapeutic approaches to treat patients with these conditions.
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Affiliation(s)
- Ammar Boudaka
- Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoud, P.O. Box 35, Muscat 123, Oman
- Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki 444-8787, Aichi, Japan;
- Correspondence:
| | - Makoto Tominaga
- Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki 444-8787, Aichi, Japan;
- Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki 444-8787, Aichi, Japan
- Exploratory Research Center on Life and Living Systems, Thermal Biology Group, Okazaki 444-8787, Aichi, Japan
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Distribution and Assembly of TRP Ion Channels. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1349:111-138. [PMID: 35138613 DOI: 10.1007/978-981-16-4254-8_7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In the last several decades, a large family of ion channels have been identified and studied intensively as cellular sensors for diverse physical and/or chemical stimuli. Named transient receptor potential (TRP) channels, they play critical roles in various aspects of cellular physiology. A large number of human hereditary diseases are found to be linked to TRP channel mutations, and their dysregulations lead to acute or chronical health problems. As TRP channels are named and categorized mostly based on sequence homology rather than functional similarities, they exhibit substantial functional diversity. Rapid advances in TRP channel study have been made in recent years and reported in a vast body of literature; a summary of the latest advancements becomes necessary. This chapter offers an overview of current understandings of TRP channel distribution and subunit assembly.
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Yu M, Chang C, Undem BJ, Yu S. Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus. Molecules 2021; 26:3929. [PMID: 34203134 PMCID: PMC8271978 DOI: 10.3390/molecules26133929] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 01/14/2023] Open
Abstract
Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.
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Affiliation(s)
| | | | | | - Shaoyong Yu
- Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, 720 Rutland Ave, Baltimore, MD 21205, USA; (M.Y.); (C.C.); (B.J.U.)
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Jaffal SM, Abbas MA. TRP channels in COVID-19 disease: Potential targets for prevention and treatment. Chem Biol Interact 2021; 345:109567. [PMID: 34166652 PMCID: PMC8217345 DOI: 10.1016/j.cbi.2021.109567] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/15/2021] [Accepted: 06/21/2021] [Indexed: 01/05/2023]
Abstract
Coronavirus disease 2019 [COVID-19] is a global health threat caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV2] that requires two proteins for entry: angiotensin-converting enzyme 2 [ACE2] and -membrane protease serine 2 [TMPRSS2]. Many patients complain from pneumonia, cough, fever, and gastrointestinal (GI) problems. Notably, different TRP channels are expressed in various tissues infected by SARS-CoV-2. TRP channels are cation channels that show a common architecture with high permeability to calcium [Ca2+] in most sub-families. Literature review shed light on the possible role of TRP channels in COVID-19 disease. TRP channels may take part in inflammation, pain, fever, anosmia, ageusia, respiratory, cardiovascular, GI and neurological complications related to COVID-19. Also, TRP channels could be the targets for many active compounds that showed effectiveness against SARS-CoV-2. Desensitization or blocking TRP channels by antibodies, aptamers, small molecules or venoms can be an option for COVID-19 prevention and future treatment. This review provides insights into the involvement of TRP channels in different symptoms and mechanisms of SARS-CoV-2 , potential treatments targeting these channels and highlights missing gaps in literature.
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Affiliation(s)
- Sahar M Jaffal
- Department of Biological Sciences, Faculty of Science, The University of Jordan, 11942, Amman, Jordan.
| | - Manal A Abbas
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, 19328, Amman, Jordan; Pharmacological and Diagnostic Research Center, Al-Ahliyya Amman University, 19328, Amman, Jordan
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Gottesman-Katz L, Latorre R, Vanner S, Schmidt BL, Bunnett NW. Targeting G protein-coupled receptors for the treatment of chronic pain in the digestive system. Gut 2021; 70:970-981. [PMID: 33272979 PMCID: PMC9716638 DOI: 10.1136/gutjnl-2020-321193] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 10/21/2020] [Accepted: 11/07/2020] [Indexed: 12/14/2022]
Abstract
Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.
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Affiliation(s)
- Lena Gottesman-Katz
- Molecular Pathobiology, New York University, New York, New York, USA,Division of Pediatric Gastroenterology, Columbia University Medical Center/New York Presbyterian, New York, New York, USA
| | - Rocco Latorre
- Molecular Pathobiology, New York University, New York, New York, USA
| | - Stephen Vanner
- Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queens University, Kingston, Ontario, Canada
| | - Brian L Schmidt
- Bluestone Center, New York University, New York, New York, USA
| | - Nigel W Bunnett
- Molecular Pathobiology, New York University, New York, New York, USA
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van den Berg MPM, Nijboer-Brinksma S, Bos IST, van den Berge M, Lamb D, van Faassen M, Kema IP, Gosens R, Kistemaker LEM. The novel TRPA1 antagonist BI01305834 inhibits ovalbumin-induced bronchoconstriction in guinea pigs. Respir Res 2021; 22:48. [PMID: 33557843 PMCID: PMC7871391 DOI: 10.1186/s12931-021-01638-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 01/25/2021] [Indexed: 01/05/2023] Open
Abstract
Background Asthma is a chronic respiratory disease in which the nervous system plays a central role. Sensory nerve activation, amongst others via Transient Receptor Potential Ankyrin 1 (TRPA1) channels, contributes to asthma characteristics including cough, bronchoconstriction, mucus secretion, airway hyperresponsiveness (AHR) and inflammation. In the current study, we evaluated the efficacy of the novel TRPA1 antagonist BI01305834 against AHR and inflammation in guinea-pig models of asthma. Methods First, a pilot study was performed in a guinea-pig model of allergic asthma to find the optimal dose of BI01305834. Next, the effect of BI01305834 on (1) AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), (2) magnitude of EAR and LAR and (3) airway inflammation was assessed. Precision-cut lung slices and trachea strips were used to investigate the bronchoprotective and bronchodilating-effect of BI01305834. Statistical evaluation of differences of in vivo data was performed using a Mann–Whitney U test or One-way nonparametric Kruskal–Wallis ANOVA, for ex vivo data One- or Two-way ANOVA was used, all with Dunnett’s post-hoc test where appropriate. Results A dose of 1 mg/kg BI01305834 was selected based on AHR and exposure data in blood samples from the pilot study. In the subsequent study, 1 mg/kg BI01305834 inhibited AHR after the EAR, and the development of EAR and LAR elicited by ovalbumin in ovalbumin-sensitized guinea pigs. BI01305834 did not inhibit allergen-induced total and differential cells in the lavage fluid and interleukin-13 gene expression in lung homogenates. Furthermore, BI01305834 was able to inhibit allergen and histamine-induced airway narrowing in guinea-pig lung slices, without affecting histamine release, and reverse allergen-induced bronchoconstriction in guinea-pig trachea strips. Conclusions TRPA1 inhibition protects against AHR and the EAR and LAR in vivo and allergen and histamine-induced airway narrowing ex vivo, and reverses allergen-induced bronchoconstriction independently of inflammation. This effect was partially dependent upon histamine, suggesting a neuronal and possible non-neuronal role for TRPA1 in allergen-induced bronchoconstriction.
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Affiliation(s)
- Mariska P M van den Berg
- Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.,Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Susan Nijboer-Brinksma
- Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.,Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - I Sophie T Bos
- Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.,Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Maarten van den Berge
- Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - David Lamb
- Immunology + Respiratory, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Martijn van Faassen
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Ido P Kema
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Reinoud Gosens
- Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.,Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Loes E M Kistemaker
- Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands. .,Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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14
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Dong R, Zhang T, Wei W, Zhang M, Chen Q, Xu X, Yu L, Qiu Z. A Cold Environment Aggravates Cough Hyperreactivity in Guinea Pigs With Cough by Activating the TRPA1 Signaling Pathway in Skin. Front Physiol 2020; 11:833. [PMID: 32982765 PMCID: PMC7481366 DOI: 10.3389/fphys.2020.00833] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 06/22/2020] [Indexed: 12/23/2022] Open
Abstract
Cough exacerbation in cold environments is a characteristic feature of patients with chronic cough. There is consensus that inhalation of cold air stimulates cough receptors but this idea is not consistent with the fact that cold air is usually unable to directly enter the lower airway. To elucidate the effects of cold environments and transient receptor potential ankyrin 1 (TRPA1) on cough, we compared cough reactivity, airway inflammation, and TRPA1 expression in guinea pigs with chronic cough induced by the repeated inhalation of citric acid for 15 days. The guinea pigs were exposed to cold environments for three consecutive days from day 13 to 15. Repeated inhalation of citric acid increased cough reactivity to inhaled cinnamaldehyde. We found that exposure to cold environments further aggravated cough hyperreactivity in guinea pigs with chronic cough, but not in normal guinea pigs. Cough hyperreactivity was promoted when the whole body and trunk-limbs, but not the heads, of the guinea pigs were exposed to cold environments, and abolished by pretreating the skin through immersion in the TRPA1 antagonist, HC-030031. Substance P levels in bronchoalveolar lavage fluid, and TRPA1 expression in the trachea and skin, were increased in guinea pigs when the whole body and trunk-limbs, rather than the head, were exposed to cold environments. However, this trend was also abolished by pretreatment of the skin via immersion in HC-030031. Similar changes in TRPA1 expression were also detected in the sensory fibers of the trachea and skin, as identified by immunofluorescence and laser-scanning confocal microscopy analysis. These results suggest that exaggerated cough hyperreactivity induced by cold environments may be related to activation of the cold-sensing TRPA1 signaling pathway in the skin, rather than the inhalation of cold air.
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Affiliation(s)
- Ran Dong
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tongyangzi Zhang
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Weili Wei
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Mengru Zhang
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiang Chen
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xianghuai Xu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Li Yu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhongmin Qiu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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15
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Hossain MZ, Ando H, Unno S, Kitagawa J. Targeting Chemosensory Ion Channels in Peripheral Swallowing-Related Regions for the Management of Oropharyngeal Dysphagia. Int J Mol Sci 2020; 21:E6214. [PMID: 32867366 PMCID: PMC7503421 DOI: 10.3390/ijms21176214] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 08/24/2020] [Accepted: 08/26/2020] [Indexed: 12/22/2022] Open
Abstract
Oropharyngeal dysphagia, or difficulty in swallowing, is a major health problem that can lead to serious complications, such as pulmonary aspiration, malnutrition, dehydration, and pneumonia. The current clinical management of oropharyngeal dysphagia mainly focuses on compensatory strategies and swallowing exercises/maneuvers; however, studies have suggested their limited effectiveness for recovering swallowing physiology and for promoting neuroplasticity in swallowing-related neuronal networks. Several new and innovative strategies based on neurostimulation in peripheral and cortical swallowing-related regions have been investigated, and appear promising for the management of oropharyngeal dysphagia. The peripheral chemical neurostimulation strategy is one of the innovative strategies, and targets chemosensory ion channels expressed in peripheral swallowing-related regions. A considerable number of animal and human studies, including randomized clinical trials in patients with oropharyngeal dysphagia, have reported improvements in the efficacy, safety, and physiology of swallowing using this strategy. There is also evidence that neuroplasticity is promoted in swallowing-related neuronal networks with this strategy. The targeting of chemosensory ion channels in peripheral swallowing-related regions may therefore be a promising pharmacological treatment strategy for the management of oropharyngeal dysphagia. In this review, we focus on this strategy, including its possible neurophysiological and molecular mechanisms.
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Affiliation(s)
- Mohammad Zakir Hossain
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan;
| | - Hiroshi Ando
- Department of Biology, School of Dentistry, Matsumoto Dental University, 1780 Gobara, Hirooka, Shiojiri, Nagano 399-0781, Japan;
| | - Shumpei Unno
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan;
| | - Junichi Kitagawa
- Department of Oral Physiology, School of Dentistry, Matsumoto Dental University, 1780 Gobara Hirooka, Shiojiri, Nagano 399-0781, Japan;
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16
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Sun DL, Qi YX, Yang T, Lin YY, Li SM, Li YJ, Xu QW, Sun YB, Li WM, Chen XZ, Xu PY. Early oral nutrition improves postoperative ileus through the TRPA1/CCK1-R-mediated mast cell-nerve axis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:179. [PMID: 32309326 PMCID: PMC7154392 DOI: 10.21037/atm.2020.01.95] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background The mechanism of early oral nutrition that regulates the mast cell-nerve axis to improve postoperative ileus (POI) remains unclear. This study aims to investigate whether early oral nutrition can improve POI through Transient receptor potential ankyrin-1 (TRPA1)/cholecystokinin 1 receptor (CCK1-R) in the mast cell-nerve axis. Methods Experiment 1: Male Sprague-Dawley (SD) rats were randomly divided into the TRPA1 inhibitor + oral nutrition group (TI + ON + POI), oral nutrition group (ON + POI), POI group (POI) and sham surgery group (Sham). Nine rats in each group were treated. Experiment 2: Primary cultures of mast cells and dorsal root ganglion cells were created, and a non-contact co-culture system was established. The cells were divided into the dorsal root ganglion (DRG) group, mast cell group, DRG + mast cell group, TRPA1 inhibitor or enhancer group, mast cell stabilizer or enhancer group, CCK1-R inhibitor or enhancer group. The results of expression of TRPA1, CCK1-R and histamine in colon tissue, portal vein blood, supernatant or dorsal root ganglia, intestinal transport test and mast cell morphology were analysed. Results In experiment 1, Early oral nutrition could alleviate the degranulation and activation of mast cells and alleviate the inflammatory reaction of intestinal wall muscles (P<0.05). Early oral nutrition improved POI by stabilizing mast cells with TRPA1. TRPA1 inhibitor decreased CCK1-R concentrations in portal vein blood and CCK1-R expression in colonic smooth muscle (P<0.05). In experiment 2, the change in mast cell function regulated the secretion of CCK1-R by neurons, CCK1-R negatively regulated the degranulation and activation of mast cells (P<0.05), and mast cells positively regulated the expression of TRPA1 protein in DRG (P<0.05). Conclusions Early enteral nutrition can improve POI through the TRPA1/CCK1-R-mediated mast cell-nerve axis. TRPA1 positively regulates CCK1-R to stabilize mast cells, but TRPA1 is not the target of the downstream CCK1-R pathway.
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Affiliation(s)
- Da-Li Sun
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Yu-Xing Qi
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Ting Yang
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Yue-Ying Lin
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Shu-Min Li
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Yi-Jun Li
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Qing-Wen Xu
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Yan-Bo Sun
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Wei-Ming Li
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Xiong-Zhi Chen
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
| | - Peng-Yuan Xu
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.,Yunnan Research Center for Surgical Clinical Nutrition, Kunming 650101, China
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17
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Talavera K, Startek JB, Alvarez-Collazo J, Boonen B, Alpizar YA, Sanchez A, Naert R, Nilius B. Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease. Physiol Rev 2019; 100:725-803. [PMID: 31670612 DOI: 10.1152/physrev.00005.2019] [Citation(s) in RCA: 253] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The transient receptor potential ankyrin (TRPA) channels are Ca2+-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH2 terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.
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Affiliation(s)
- Karel Talavera
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Justyna B Startek
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Julio Alvarez-Collazo
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Brett Boonen
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Yeranddy A Alpizar
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Alicia Sanchez
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Robbe Naert
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Bernd Nilius
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
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18
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D'Auria E, Salvatore S, Pozzi E, Mantegazza C, Sartorio MUA, Pensabene L, Baldassarre ME, Agosti M, Vandenplas Y, Zuccotti G. Cow's Milk Allergy: Immunomodulation by Dietary Intervention. Nutrients 2019; 11:1399. [PMID: 31234330 PMCID: PMC6627562 DOI: 10.3390/nu11061399] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 06/14/2019] [Accepted: 06/17/2019] [Indexed: 12/26/2022] Open
Abstract
Cow's milk proteins cause allergic symptoms in 2% to 3% of all infants. In these individuals, the physiological mechanism of tolerance is broken with subsequent possible sensitization to antigens, which can lead eventually to allergic responses. The present review aims to provide an overview of different aspects of immune modulation by dietary intervention in cow's milk allergy (CMA). It focuses on pathogenetic mechanisms of different CMA related disorders, e.g., gastroesophageal reflux and eosinophilic esophagitis, highlighting the role of dietary management on innate and adaptive immune systems. The traditional dietary management of CMA has greatly changed in the last years, moving from a passive approach, consisting of an elimination diet to relieve symptoms, to a "proactive" one, meaning the possibility to actively modulate the immune system. Thus, new insights into the role of hydrolysates and baked milk in immunomodulation are addressed here. Additionally, nutritional components, such as pre- and probiotics, may target the immune system via microbiota, offering a possible road map for new CMA prevention and treatment strategies.
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Affiliation(s)
- Enza D'Auria
- Department of Pediatrics, Vittore Buzzi Children's Hospital-University of Milan, 20154 Milan, Italy.
| | - Silvia Salvatore
- Department of Pediatrics, Ospedale "F. Del Ponte", University of Insubria, 21100 Varese, Italy.
| | - Elena Pozzi
- Department of Pediatrics, Vittore Buzzi Children's Hospital-University of Milan, 20154 Milan, Italy.
| | - Cecilia Mantegazza
- Department of Pediatrics, Vittore Buzzi Children's Hospital-University of Milan, 20154 Milan, Italy.
| | - Marco Ugo Andrea Sartorio
- Department of Pediatrics, Vittore Buzzi Children's Hospital-University of Milan, 20154 Milan, Italy.
| | - Licia Pensabene
- Department of Medical and Surgical Sciences, Pediatric Unit, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
| | - Maria Elisabetta Baldassarre
- Neonatology and Neonatal Intensive Care Unit, Department of Biomedical Science and Human Oncology, "Aldo Moro" University of Bari, P.zza Giulio Cesare 11, 70124 Bari, Italy.
| | - Massimo Agosti
- Department of Pediatrics, Ospedale "F. Del Ponte", University of Insubria, 21100 Varese, Italy.
| | - Yvan Vandenplas
- KidZ Health Castle, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
| | - GianVincenzo Zuccotti
- Department of Pediatrics, Vittore Buzzi Children's Hospital-University of Milan, 20154 Milan, Italy.
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19
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Mucosal permeability and mast cells as targets for functional gastrointestinal disorders. Curr Opin Pharmacol 2018; 43:66-71. [PMID: 30216901 DOI: 10.1016/j.coph.2018.08.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Revised: 08/22/2018] [Accepted: 08/25/2018] [Indexed: 02/08/2023]
Abstract
The intestinal mucosa is constantly exposed to harmful luminal content, and uptake is closely controlled and regulated by neuro-immune factors. If control is broken, it might lead to ongoing enhanced mucosal permeability, potentially resulting in functional gastrointestinal disorders. The importance of mast cells in the regulation of the mucosal barrier has become obvious, and increased numbers and more activated mast cells have been observed in irritable bowel syndrome, functional dyspepsia and gastroesophageal reflux disease. To target the disturbed mucosal permeability, directly or via mast cells, is therefore currently of major interest. For example, administration of mast cell stabilizers and probiotics have shown promising effects in patients with functional gastrointestinal disorders.
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20
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Selective killing of proinflammatory synovial fibroblasts via activation of transient receptor potential ankyrin (TRPA1). Biochem Pharmacol 2018; 154:293-302. [PMID: 29803505 DOI: 10.1016/j.bcp.2018.05.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/22/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Studies in rheumatoid arthritis synovial fibroblasts (RASF) demonstrated the expression of several transient receptor potential channels (TRP) such as TRPV1, TRPV2, TRPV4, TRPA1 and TRPM8. Upon ligation, these receptors increase intracellular calcium but they have also been linked to modulation of inflammation in several cell types. TNF was shown to increase the expression of TRPA1, the receptor for mustard oil and environmental poisons in SF, but the functional consequences have not been investigated yet. METHODS TRPA1 was detected by immunocytochemistry, western blot and cell-based ELISA. Calcium measurements were conducted in a multimode reader. Cell viability was assessed by quantification of lactate dehydrogenase (LDH) in culture supernatants and "RealTime-Glo" luminescent assays. IL-6 and IL-8 production by SF was quantified by ELISA. Proliferation was determined by cell titer blue incorporation. RESULTS After 72 h, mimicking proinflammatory conditions by the innate cytokine TNF up-regulated TRPA1 protein levels in RASF which was accompanied by increased sensitivity to TRPA1 agonists AITC and polygodial. Under unstimulated conditions, polygodial elicited calcium flux only in the highest concentrations used (50 µM and 25 µM). TNF preincubation substantially lowered the activation threshold for polygodial (from 25 µM to 1 µM). In the absence of TNF pre-stimulation, only polygodial in high concentrations was able to reduce viability of synovial fibroblasts as determined by a real-time viability assay. However, following TNF preincubation, stimulation of TRPA1 led to a fast (<30 min) viability loss by necrosis of synovial fibroblasts. TRPA1 activation was also associated with decreased proliferation of RASFs, an effect that was also substantially enhanced by TNF preincubation. On the functional level, IL-6 and IL-8 production was attenuated by the TRPA1 antagonist A967079 but also polygodial, although the latter mediated this effect by reducing cell viability. CONCLUSION Simulating inflamed conditions by preincubation of synovial fibroblasts with TNF up-regulates and sensitizes TRPA1. Subsequent activation of TRPA1 increases calcium flux and substantially reduces cell viability by inducing necrosis. Since TRPA1 agonists in the lower concentration range only show effects in TNF-stimulated RASF, this cation channel might be an attractive therapeutic target in chronic inflammation to selectively reduce the activity of proinflammatory SF in the joint.
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21
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Moore C, Gupta R, Jordt SE, Chen Y, Liedtke WB. Regulation of Pain and Itch by TRP Channels. Neurosci Bull 2018; 34:120-142. [PMID: 29282613 PMCID: PMC5799130 DOI: 10.1007/s12264-017-0200-8] [Citation(s) in RCA: 215] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 10/27/2017] [Indexed: 02/07/2023] Open
Abstract
Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily (TRPV1, TRPV3, and TRPV4), and finally members of the melastatin group (TRPM2, TRPM3, and TRPM8). Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory compounds targeting specific pain/itch-TRPs so that physiological protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1-modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accomplished via simple dosing strategies, and also by incorporating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.
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Affiliation(s)
- Carlene Moore
- Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Rupali Gupta
- Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Sven-Eric Jordt
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Yong Chen
- Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA.
| | - Wolfgang B Liedtke
- Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA.
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA.
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22
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Wu SW, Fowler DK, Shaffer FJ, Lindberg JEM, Peters JH. Ethyl Vanillin Activates TRPA1. J Pharmacol Exp Ther 2017; 362:368-377. [PMID: 28620120 PMCID: PMC5539581 DOI: 10.1124/jpet.116.239384] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 05/19/2017] [Indexed: 01/11/2023] Open
Abstract
The nonselective cation channel transient receptor potential ankryn subtype family 1 (TRPA1) is expressed in neurons of dorsal root ganglia and trigeminal ganglia and also in vagal afferent neurons that innervate the lungs and gastrointestinal tract. Many TRPA1 agonists are reactive electrophilic compounds that form covalent adducts with TRPA1. Allyl isothiocyanate (AITC), the common agonist used to identify TRPA1, contains an electrophilic group that covalently binds with cysteine residues of TRPA1 and confers a structural change on the channel. There is scientific motivation to identify additional compounds that can activate TRPA1 with different mechanisms of channel gating. We provide evidence that ethyl vanillin (EVA) is a TRPA1 agonist. Using fluorescent calcium imaging and whole-cell patch-clamp electrophysiology on dissociated rat vagal afferent neurons and TRPA1-transfected COS-7 cells, we discovered that EVA activates cells also activated by AITC. Both agonists display similar current profiles and conductances. Pretreatment with A967079, a selective TRPA1 antagonist, blocks the EVA response as well as the AITC response. Furthermore, EVA does not activate vagal afferent neurons from TRPA1 knockout mice, showing selectivity for TRPA1 in this tissue. Interestingly, EVA appears to be pharmacologically different from AITC as a TRPA1 agonist. When AITC is applied before EVA, the EVA response is occluded. However, they both require intracellular oxidation to activate TRPA1. These findings suggest that EVA activates TRPA1 but via a distinct mechanism that may provide greater ease for study in native systems compared with AITC and may shed light on differential modes of TRPA1 gating by ligand types.
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Affiliation(s)
- Shaw-Wen Wu
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington (D.K.F., F.J.S., J.E.M.L., J.H.P.); and Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida (S.-w.W.)
| | - Daniel K Fowler
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington (D.K.F., F.J.S., J.E.M.L., J.H.P.); and Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida (S.-w.W.)
| | - Forrest J Shaffer
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington (D.K.F., F.J.S., J.E.M.L., J.H.P.); and Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida (S.-w.W.)
| | - Jonathon E M Lindberg
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington (D.K.F., F.J.S., J.E.M.L., J.H.P.); and Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida (S.-w.W.)
| | - James H Peters
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington (D.K.F., F.J.S., J.E.M.L., J.H.P.); and Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida (S.-w.W.)
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23
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Lucena F, Foletto V, Mascarin LZ, Tonussi CR. Analgesic and anti-edematogenic effects of oral trypsin were abolished after subdiaphragmatic vagotomy and spinal monoaminergic inhibition in rats. Life Sci 2016; 166:60-65. [PMID: 27729269 DOI: 10.1016/j.lfs.2016.10.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 09/29/2016] [Accepted: 10/07/2016] [Indexed: 01/07/2023]
Abstract
AIMS Rheumatoid arthritis brings great burdens to the patients. In addition to the highly expensive treatment, they are commonly associated with severe side effects. In such context, the research for safe and affordable treatments is needed. MAIN METHODS Arthritis was induced by CFA (0.5mg/mL) in female wistar rats. Trypsin was given p.o. (2.95mg/kg; 2mL) 24h after the intra-articular CFA injection. Articular incapacitation was measured daily by counting the paw elevation time (PET; s) during 1-min periods of stimulated walk, throughout the 7-days after intra-articular CFA injection. Articular diameter (AD) was accessed just after each PET measurement, taken the difference between naïve and diseased knee-joint diameter (cm). KEY FINDINGS The present study showed that orally administered trypsin was able to reduce nociception and edema, effects that could be observed throughout the evaluation period. These effect, however, were not observed in animals underwent subdiaphragmatic vagotomy, suggesting a vagal mediation for trypsin effects. Likewise, these effects were blocked in rats which received intrathecal injection of the neurotoxins 5,7-dihydroxytryptamine or 6-hydroxydopamine, suggesting the involvement of spinal amines from axon terminals. SIGNIFICANCE The present study proposes that oral trypsin may cause vagal activation, followed by the activation of descending inhibitory pathways and such mechanism may lead to a novel approach for the treatment of arthritis.
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Affiliation(s)
- Flora Lucena
- Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
| | - Vanessa Foletto
- Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
| | - Lucas Zanon Mascarin
- Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
| | - Carlos Rogério Tonussi
- Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil.
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24
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Shima T, Shiina T, Naitou K, Nakamori H, Sano Y, Shimizu Y. Does the capsaicin-sensitive local neural circuit constitutively regulate vagally evoked esophageal striated muscle contraction in rats? J Physiol Sci 2016; 66:105-11. [PMID: 26424590 PMCID: PMC10717485 DOI: 10.1007/s12576-015-0401-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 09/07/2015] [Indexed: 01/06/2023]
Abstract
To determine whether a capsaicin-sensitive local neural circuit constitutively modulates vagal neuromuscular transmission in the esophageal striated muscle or whether the neural circuit operates in a stimulus-dependent manner, we compared the motility of esophageal preparations isolated from intact rats with those in which capsaicin-sensitive neurons had been destroyed. Electrical stimulation of the vagus nerve trunk evoked contractile responses in the esophagus isolated from a capsaicin-treated rat in a manner similar to those in the esophagus from a control rat. No obvious differences were observed in the inhibitory effects of D-tubocurarine on intact and capsaicin-treated rat esophageal motility. Destruction of the capsaicin-sensitive neurons did not significantly affect latency, time to peak and duration of a vagally evoked twitch-like contraction. These findings indicate that the capsaicin-sensitive neural circuit does not operate constitutively but rather is activated in response to an applied stimulus.
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Affiliation(s)
- Takeshi Shima
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Takahiko Shiina
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
| | - Kiyotada Naitou
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Hiroyuki Nakamori
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Yuuki Sano
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Yasutake Shimizu
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
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25
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Brozmanova M, Mazurova L, Ru F, Tatar M, Hu Y, Yu S, Kollarik M. Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers. Am J Physiol Gastrointest Liver Physiol 2016; 310:G215-23. [PMID: 26564719 PMCID: PMC4971813 DOI: 10.1152/ajpgi.00350.2014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 11/09/2015] [Indexed: 01/31/2023]
Abstract
Clinical studies indicate that adenosine contributes to esophageal mechanical hypersensitivity in some patients with pain originating in the esophagus. We have previously reported that the esophageal vagal nodose C fibers express the adenosine A2A receptor. Here we addressed the hypothesis that stimulation of the adenosine A2A receptor induces mechanical sensitization of esophageal C fibers by a mechanism involving transient receptor potential A1 (TRPA1). Extracellular single fiber recordings of activity originating in C-fiber terminals were made in the ex vivo vagally innervated guinea pig esophagus. The adenosine A2A receptor-selective agonist CGS21680 induced robust, reversible sensitization of the response to esophageal distention (10-60 mmHg) in a concentration-dependent fashion (1-100 nM). At the half-maximally effective concentration (EC50: ≈3 nM), CGS21680 induced an approximately twofold increase in the mechanical response without causing an overt activation. This sensitization was abolished by the selective A2A antagonist SCH58261. The adenylyl cyclase activator forskolin mimicked while the nonselective protein kinase inhibitor H89 inhibited mechanical sensitization by CGS21680. CGS21680 did not enhance the response to the purinergic P2X receptor agonist α,β-methylene-ATP, indicating that CGS21680 does not nonspecifically sensitize to all stimuli. Mechanical sensitization by CGS21680 was abolished by pretreatment with two structurally different TRPA1 antagonists AP18 and HC030031. Single cell RT-PCR and whole cell patch-clamp studies in isolated esophagus-specific nodose neurons revealed the expression of TRPA1 in A2A-positive C-fiber neurons and demonstrated that CGS21682 potentiated TRPA1 currents evoked by allylisothiocyanate. We conclude that stimulation of the adenosine A2A receptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1.
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Affiliation(s)
- M. Brozmanova
- 1Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and
| | - L. Mazurova
- 1Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and
| | - F. Ru
- 2Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - M. Tatar
- 1Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and
| | - Y. Hu
- 2Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - S. Yu
- 2Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - M. Kollarik
- 1Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; and ,2Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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26
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Ferreira LGB, Faria RX. TRPing on the pore phenomenon: what do we know about transient receptor potential ion channel-related pore dilation up to now? J Bioenerg Biomembr 2016; 48:1-12. [PMID: 26728159 DOI: 10.1007/s10863-015-9634-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Accepted: 12/02/2015] [Indexed: 01/06/2023]
Abstract
Ion channels allow for rapid ion diffusion through the plasma membrane. In some conditions, ion channels induce changes in the critical plasma membrane permeability that permit 900-Da solutes to enter cells. This process is known as the pore phenomenon. Some transient receptor potential (TRP) channel subtypes have been highlighted such as the P2X7 receptor, plasma membrane VDAC-1 channel, and pannexin hemichannels. The TRP ion channels are considered multimodal transducers that respond to several kinds of stimuli. In addition, many TRP channel subtypes are involved in physiological and pathophysiological processes such as inflammation, pain, and cancer. The TRPA1, TRPM8, and TRPV1-4 subtypes have been shown to promote large-molecular-weight solute uptake, including impermeable fluorescent dyes, QX-314 hydrophilic lidocaine derivative, gabapentin, and antineoplastic drugs. This review discusses the current knowledge of TRP-associated pores and encourages scientists to study their features and explore them as novel therapeutic tools.
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Affiliation(s)
- L G B Ferreira
- Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Av. Brasil, n° 4365, Manguinhos, CEP 21045-900, Rio de Janeiro, Brazil.
| | - R X Faria
- Laboratory of Cellular Communication, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil, n° 4365, Manguinhos, CEP 21045-900, Rio de Janeiro, Brazil
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27
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Hennel M, Brozmanova M, Kollarik M. Cough reflex sensitization from esophagus and nose. Pulm Pharmacol Ther 2015; 35:117-21. [PMID: 26498387 DOI: 10.1016/j.pupt.2015.10.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 10/14/2015] [Accepted: 10/18/2015] [Indexed: 01/07/2023]
Abstract
The diseases of the esophagus and nose are among the major factors contributing to chronic cough although their role in different patient populations is debated. Studies in animal models and in humans show that afferent C-fiber activators applied on esophageal or nasal mucosa do not initiate cough, but enhance cough induced by inhaled irritants. These results are consistent with the hypothesis that activation of esophageal and nasal C-fibers contribute to cough reflex hypersensitivity observed in chronic cough patients with gastroesophageal reflux disease (GERD) and chronic rhinitis, respectively. The afferent nerves mediating cough sensitization from the esophagus are probably the neural crest-derived vagal jugular C-fibers. In addition to their responsiveness to high concentration of acid typical for gastroesophageal reflux (pH < 5), esophageal C-fibers also express receptors for activation by weakly acidic reflux such as receptors highly sensitive to acid and receptors for bile acids. The nature of sensory pathways from the nose and their activators relevant for cough sensitization are less understood. Increased cough reflex sensitivity was also reported in many patients with GERD or rhinitis who do not complain of cough indicating that additional endogenous or exogenous factors may be required to develop chronic coughing in these diseases.
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Affiliation(s)
- Michal Hennel
- Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia
| | - Mariana Brozmanova
- Department of Pathophysiology and Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia
| | - Marian Kollarik
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, USA.
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28
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Yu X, Yu M, Liu Y, Yu S. TRP channel functions in the gastrointestinal tract. Semin Immunopathol 2015; 38:385-96. [PMID: 26459157 DOI: 10.1007/s00281-015-0528-y] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 09/07/2015] [Indexed: 12/14/2022]
Abstract
Transient receptor potential (TRP) channels are predominantly distributed in both somatic and visceral sensory nervous systems and play a crucial role in sensory transduction. As the largest visceral organ system, the gastrointestinal (GI) tract frequently accommodates external inputs, which stimulate sensory nerves to initiate and coordinate sensory and motor functions in order to digest and absorb nutrients. Meanwhile, the sensory nerves in the GI tract are also able to detect potential tissue damage by responding to noxious irritants. This nocifensive function is mediated through specific ion channels and receptors expressed in a subpopulation of spinal and vagal afferent nerve called nociceptor. In the last 18 years, our understanding of TRP channel expression and function in GI sensory nervous system has been continuously improved. In this review, we focus on the expressions and functions of TRPV1, TRPA1, and TRPM8 in primary extrinsic afferent nerves innervated in the esophagus, stomach, intestine, and colon and briefly discuss their potential roles in relevant GI disorders.
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Affiliation(s)
- Xiaoyun Yu
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, Room 945, 720 Rutland Ave, Baltimore, MD, 21205, USA
| | - Mingran Yu
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, Room 945, 720 Rutland Ave, Baltimore, MD, 21205, USA
| | - Yingzhe Liu
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, Room 945, 720 Rutland Ave, Baltimore, MD, 21205, USA
| | - Shaoyong Yu
- Division of Gastroenterology & Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Research Building, Room 945, 720 Rutland Ave, Baltimore, MD, 21205, USA.
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29
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Song J, Zhang L, Bai T, Qian W, Li R, Hou X. Mast Cell-dependent Mesenteric Afferent Activation by Mucosal Supernatant From Different Bowel Segments of Guinea Pigs With Post-infectious Irritable Bowel Syndrome. J Neurogastroenterol Motil 2015; 21:236-246. [PMID: 25843076 PMCID: PMC4398249 DOI: 10.5056/jnm14095] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 12/08/2014] [Accepted: 12/14/2014] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS Mesenteric afferent nerves (MANs) play a pivotal role in the visceral-nociceptive perception. Inappropriate activation of MANs may be involved in the pathogenesis of post-infectious irritable bowel syndrome (PI-IBS). However, the underlying mechanisms remain unclear. We assessed the effects of mucosal mediators from different bowel segments of guinea pigs with PI-IBS on MAN firing and the role of mast cells. METHODS PI-IBS was induced in guinea pigs by Trichinella spiralis infection. Inflammation in terminal ileum, proximal and distal colon was scored with hematoxylin-eosin staining, and mast cell infiltration was assessed with immunofluorescence. We determined the effects of supernatant extracted from the mucosa of different bowel segments of PI-IBS on MANs activity, and assessed the role of mast cells in this process. RESULTS Eight weeks after infection, intestinal inflammation resolved, whereas mast cell numbers increased significantly in terminal ileum and proximal colon (P < 0.05) compared with findings in controls. Mucosal supernatant from different bowel segments of PI-IBS models, but not from controls, significantly enhanced the frequency of MAN firing (terminal ileum 41.01 ± 7.60 Hz vs. 26.55 ± 0.67 Hz, P = 0.001; proximal colon 45.90 ± 11.20 Hz vs. 30.88 ± 6.92 Hz, P = 0.002; distal colon 48.25 ± 9.70 Hz vs. 29.47 ± 6.13 Hz, P < 0.001). In addition, the excitatory effects were inhibited by mast cell stabilizer Nasmil (terminal ileum, 32.71 ± 2.52 Hz, P = 0.030; proximal colon, 30.94 ± 4.44 Hz, P = 0.002; distal colon, 27.15 ± 5.83 Hz, P < 0.001). CONCLUSIONS Supernatant from the intestinal mucosa of different bowel segments of PI-IBS models markedly enhanced the MAN firing in a mast cell-dependent manner, indicating that mast cell-mediated MAN activation plays an important role in the pathogenesis of PI-IBS.
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Affiliation(s)
- Jun Song
- Division of Gastroenterology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan,
China
| | - Lei Zhang
- Division of Gastroenterology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan,
China
| | - Tao Bai
- Division of Gastroenterology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan,
China
| | - Wei Qian
- Division of Gastroenterology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan,
China
| | - Rui Li
- Division of Gastroenterology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan,
China
| | - Xiaohua Hou
- Division of Gastroenterology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan,
China
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30
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Liu Z, Hu Y, Yu X, Xi J, Fan X, Tse CM, Myers AC, Pasricha PJ, Li X, Yu S. Allergen challenge sensitizes TRPA1 in vagal sensory neurons and afferent C-fiber subtypes in guinea pig esophagus. Am J Physiol Gastrointest Liver Physiol 2015; 308:G482-8. [PMID: 25591867 PMCID: PMC4360047 DOI: 10.1152/ajpgi.00374.2014] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Transient receptor potential A1 (TRPA1) is a newly defined cationic ion channel, which selectively expresses in primary sensory afferent nerve, and is essential in mediating inflammatory nociception. Our previous study demonstrated that TRPA1 plays an important role in tissue mast cell activation-induced increase in the excitability of esophageal vagal nodose C fibers. The present study aims to determine whether prolonged antigen exposure in vivo sensitizes TRPA1 in a guinea pig model of eosinophilic esophagitis (EoE). Antigen challenge-induced responses in esophageal mucosa were first assessed by histological stains and Ussing chamber studies. TRPA1 function in vagal sensory neurons was then studied by calcium imaging and by whole cell patch-clamp recordings in 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal vagal nodose and jugular neurons. Extracellular single-unit recordings were performed in vagal nodose and jugular C-fiber neuron subtypes using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Antigen challenge significantly increased infiltrations of eosinophils and mast cells in the esophagus. TRPA1 agonist allyl isothiocyanate (AITC)-induced calcium influx in nodose and jugular neurons was significantly increased, and current densities in esophageal DiI-labeled nodose and jugular neurons were also significantly increased in antigen-challenged animals. Prolonged antigen challenge decreased esophageal epithelial barrier resistance, which allowed intraesophageal-infused AITC-activating nodose and jugular C fibers at their nerve endings. Collectively, these results demonstrated that prolonged antigen challenge sensitized TRPA1 in esophageal sensory neurons and afferent C fibers. This novel finding will help us to better understand the molecular mechanism underlying esophageal sensory and motor dysfunctions in EoE.
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Affiliation(s)
- Zhenyu Liu
- 1Division of Gastroenterology, Peking University Shenzhen Hospital, Shenzhen, China; ,2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
| | - Youtian Hu
- 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
| | - Xiaoyun Yu
- 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
| | - Jiefeng Xi
- 3Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Xiaoming Fan
- 4Division of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Chung-Ming Tse
- 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
| | - Allen C. Myers
- 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
| | - Pankaj J. Pasricha
- 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
| | - Xingde Li
- 3Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland; and
| | - Shaoyong Yu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
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31
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Dusenkova S, Ru F, Surdenikova L, Nassenstein C, Hatok J, Dusenka R, Banovcin P, Kliment J, Tatar M, Kollarik M. The expression profile of acid-sensing ion channel (ASIC) subunits ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3 in the esophageal vagal afferent nerve subtypes. Am J Physiol Gastrointest Liver Physiol 2014; 307:G922-30. [PMID: 25190475 PMCID: PMC4216991 DOI: 10.1152/ajpgi.00129.2014] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Acid-sensing ion channels (ASICs) have been implicated in esophageal acid sensing and mechanotransduction. However, insufficient knowledge of ASIC subunit expression profile in esophageal afferent nerves hampers the understanding of their role. This knowledge is essential because ASIC subunits form heteromultimeric channels with distinct functional properties. We hypothesized that the esophageal putative nociceptive C-fiber nerves (transient receptor potential vanilloid 1, TRPV1-positive) express multiple ASIC subunits and that the ASIC expression profile differs between the nodose TRPV1-positive subtype developmentally derived from placodes and the jugular TRPV1-positive subtype derived from neural crest. We performed single cell RT-PCR on the vagal afferent neurons retrogradely labeled from the esophagus. In the guinea pig, nearly all (90%-95%) nodose and jugular esophageal TRPV1-positive neurons expressed ASICs, most often in a combination (65-75%). ASIC1, ASIC2, and ASIC3 were expressed in 65-75%, 55-70%, and 70%, respectively, of both nodose and jugular TRPV1-positive neurons. The ASIC1 splice variants ASIC1a and ASIC1b and the ASIC2 splice variant ASIC2b were similarly expressed in both nodose and jugular TRPV1-positive neurons. However, ASIC2a was found exclusively in the nodose neurons. In contrast to guinea pig, ASIC3 was almost absent from the mouse vagal esophageal TRPV1-positive neurons. However, ASIC3 was similarly expressed in the nonnociceptive TRPV1-negative (tension mechanoreceptors) neurons in both species. We conclude that the majority of esophageal vagal nociceptive neurons express multiple ASIC subunits. The placode-derived nodose neurons selectively express ASIC2a, known to substantially reduce acid sensitivity of ASIC heteromultimers. ASIC3 is expressed in the guinea pig but not in the mouse vagal esophageal TRPV1-positive neurons, indicating species differences in ASIC expression.
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Affiliation(s)
- Svetlana Dusenkova
- 1Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; ,2Department of Pathophysiology, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia;
| | - Fei Ru
- 1Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland;
| | - Lenka Surdenikova
- 2Department of Pathophysiology, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia;
| | - Christina Nassenstein
- 1Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; ,6Institute of Anatomy and Cell Biology-Cardiopulmonary Neurobiology, Justus-Liebig-University, Giessen, Germany
| | - Jozef Hatok
- 3Department of Biochemistry, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia;
| | - Robert Dusenka
- 3Department of Biochemistry, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia; ,4Department of Urology, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia;
| | - Peter Banovcin
- 5Department of Gastroenterology, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia;
| | - Jan Kliment
- 4Department of Urology, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia;
| | - Milos Tatar
- 2Department of Pathophysiology, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia;
| | - Marian Kollarik
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pathophysiology, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia;
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Abstract
The gastrointestinal tract is innervated by several distinct populations of neurons, whose cell bodies either reside within (intrinsic) or outside (extrinsic) the gastrointestinal wall. Normally, most individuals are unaware of the continuous, complicated functions of these neurons. However, for patients with gastrointestinal disorders, such as IBD and IBS, altered gastrointestinal motility, discomfort and pain are common, debilitating symptoms. Although bouts of intestinal inflammation underlie the symptoms associated with IBD, increasing preclinical and clinical evidence indicates that infection and inflammation are also key risk factors for the development of other gastrointestinal disorders. Notably, a strong correlation exists between prior exposure to gut infection and symptom occurrence in IBS. This Review discusses the evidence for neuroplasticity (structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function. Such changes are evident during inflammation and, in many cases, long after healing of the damaged tissues, when the nervous system fails to reset back to normal. Neuroplasticity within distinct populations of neurons has a fundamental role in the aberrant motility, secretion and sensation associated with common clinical gastrointestinal disorders. To find appropriate therapeutic treatments for these disorders, the extent and time course of neuroplasticity must be fully appreciated.
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DeBerry JJ, Schwartz ES, Davis BM. TRPA1 mediates bladder hyperalgesia in a mouse model of cystitis. Pain 2014; 155:1280-1287. [PMID: 24704367 DOI: 10.1016/j.pain.2014.03.023] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 03/13/2014] [Accepted: 03/27/2014] [Indexed: 01/07/2023]
Abstract
Urinary bladder pain is a primary symptom associated with interstitial cystitis/painful bladder syndrome. We used systemic injections of cyclophosphamide (CYP), an alkylating antineoplastic agent, to induce cystitis and examine the roles of 2 channels previously demonstrated to be required for inflammatory visceral hyperalgesia: transient receptor potential vanilloid-1 (TRPV1) and ankyrin-1 (TRPA1). Injection of CYP (100 mg/kg, i.p.) every other day for 5 days was accompanied by bladder edema and urothelial ulceration, but without significant plasma extravasation or infiltration of neutrophils. Toluidine blue staining showed a significant increase in the number of degranulated bladder mast cells after CYP treatment. Despite this mild pathology, CYP-treated mice exhibited bladder hyperalgesia 1 day after the final injection that persisted 7 days later. Although many previous studies of visceral hyperalgesia have reported changes in dorsal root ganglion neuron TRPV1 expression and/or function, we found no change in bladder afferent TRPV1 expression or sensitivity on the basis of the percentage of bladder afferents responsive to capsaicin, including at submaximal concentrations. In contrast, the percentage of bladder afferents expressing functional TRPA1 protein (i.e., those responsive to mustard oil) increased ∼2.5-fold 1 day after CYP treatment, and remained significantly elevated 7 days later. Moreover, bladder hyperalgesia was reversed by acute treatment with the TRPA1 antagonist HC-030031 (300 mg/kg, i.p.). Our results indicate that CYP-induced bladder hyperalgesia can be induced without robust inflammation or changes in primary afferent TRPV1. However, significant changes were observed in TRPA1 expression, and blockade of TRPA1 alleviated CYP-induced bladder hyperalgesia.
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Affiliation(s)
- Jennifer J DeBerry
- Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261, USA Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA 15261, USA Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15261, USA Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Bourinet E, Altier C, Hildebrand ME, Trang T, Salter MW, Zamponi GW. Calcium-permeable ion channels in pain signaling. Physiol Rev 2014; 94:81-140. [PMID: 24382884 DOI: 10.1152/physrev.00023.2013] [Citation(s) in RCA: 240] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The detection and processing of painful stimuli in afferent sensory neurons is critically dependent on a wide range of different types of voltage- and ligand-gated ion channels, including sodium, calcium, and TRP channels, to name a few. The functions of these channels include the detection of mechanical and chemical insults, the generation of action potentials and regulation of neuronal firing patterns, the initiation of neurotransmitter release at dorsal horn synapses, and the ensuing activation of spinal cord neurons that project to pain centers in the brain. Long-term changes in ion channel expression and function are thought to contribute to chronic pain states. Many of the channels involved in the afferent pain pathway are permeable to calcium ions, suggesting a role in cell signaling beyond the mere generation of electrical activity. In this article, we provide a broad overview of different calcium-permeable ion channels in the afferent pain pathway and their role in pain pathophysiology.
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A focus on mast cells and pain. J Neuroimmunol 2013; 264:1-7. [PMID: 24125568 DOI: 10.1016/j.jneuroim.2013.09.018] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2013] [Revised: 09/17/2013] [Accepted: 09/19/2013] [Indexed: 12/13/2022]
Abstract
Mast cells (MCs) are immunocytes with secretory functions that act locally in peripheral tissues to modulate local hemodynamics, nociceptor activation and pain. They are also able to infiltrate the central nervous system (CNS), especially the spinal cord and the thalamus, but their cerebral function remains an enigma. A role in regulating the opening of the blood-brain barrier has been proposed. Paracrine-like action of MCs on synaptic transmission might also signal a modulation of the nervous system by the immune system. In this review, we examine the link between MCs and nociceptive process, at the periphery as well as in the CNS.
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Lu XL, Xu WX, Yan ZY, Qian Z, Xu B, Liu Y, Han LM, Gao RC, Li JN, Yuan M, Zhao CB, Qiao GF, Li BY. Subtype identification in acutely dissociated rat nodose ganglion neurons based on morphologic parameters. Int J Biol Sci 2013; 9:716-27. [PMID: 23904796 PMCID: PMC3729014 DOI: 10.7150/ijbs.7006] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 07/01/2013] [Indexed: 01/04/2023] Open
Abstract
Nodose ganglia are composed of A-, Ah- and C-type neurons. Despite their important roles in regulating visceral afferent function, including cardiovascular, pulmonary, and gastrointestinal homeostasis, information about subtype-specific expression, molecular identity, and function of individual ion transporting proteins is scarce. Although experiments utilizing the sliced ganglion preparation have provided valuable insights into the electrophysiological properties of nodose ganglion neuron subtypes, detailed characterization of their electrical phenotypes will require measurements in isolated cells. One major unresolved problem, however, is the difficulty to unambiguously identify the subtype of isolated nodose ganglion neurons without current-clamp recording, because the magnitude of conduction velocity in the corresponding afferent fiber, a reliable marker to discriminate subtypes in situ, can no longer be determined. Here, we present data supporting the notion that application of an algorithm regarding to microscopic structural characteristics, such as neuron shape evaluated by the ratio between shortest and longest axis, neuron surface characteristics, like membrane roughness, and axon attachment, enables specific and sensitive subtype identification of acutely dissociated rat nodose ganglion neurons, by which the accuracy of identification is further validated by electrophysiological markers and overall positive predictive rates is 89.26% (90.04%, 76.47%, and 98.21% for A-, Ah, and C-type, respectively). This approach should aid in gaining insight into the molecular correlates underlying phenotypic heterogeneity of nodose ganglia. Additionally, several critical points that help for neuron identification and afferent conduction calibration are also discussed.
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Affiliation(s)
- Xiao-Long Lu
- Department of Pharmacology, Harbin Medical University, Harbin, China
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Zhang S, Grabauskas G, Wu X, Joo MK, Heldsinger A, Song I, Owyang C, Yu S. Role of prostaglandin D2 in mast cell activation-induced sensitization of esophageal vagal afferents. Am J Physiol Gastrointest Liver Physiol 2013; 304:G908-16. [PMID: 23471341 PMCID: PMC3652067 DOI: 10.1152/ajpgi.00448.2012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Sensitization of esophageal afferents plays an important role in esophageal nociception, but the mechanism is less clear. Our previous studies demonstrated that mast cell (MC) activation releases the preformed mediators histamine and tryptase, which play important roles in sensitization of esophageal vagal nociceptive C fibers. PGD2 is a lipid mediator released by activated MCs. Whether PGD2 plays a role in this sensitization process has yet to be determined. Expression of the PGD2 DP1 and DP2 receptors in nodose ganglion neurons was determined by immunofluorescence staining, Western blotting, and RT-PCR. Extracellular recordings were performed in ex vivo esophageal-vagal preparations. Action potentials evoked by esophageal distension were compared before and after perfusion of PGD2, DP1 and DP2 receptor agonists, and MC activation, with or without pretreatment with antagonists. The effect of PGD2 on 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal nodose neurons was determined by patch-clamp recording. Our results demonstrate that DP1 and DP2 receptor mRNA and protein were expressed mainly in small- and medium-diameter neurons in nodose ganglia. PGD2 significantly increased esophageal distension-evoked action potential discharges in esophageal nodose C fibers. The DP1 receptor agonist BW 245C mimicked this effect. PGD2 directly sensitized DiI-labeled esophageal nodose neurons by decreasing the action potential threshold. Pretreatment with the DP1 receptor antagonist BW A868C significantly inhibited PGD2 perfusion- or MC activation-induced increases in esophageal distension-evoked action potential discharges in esophageal nodose C fibers. In conclusion, PGD2 plays an important role in MC activation-induced sensitization of esophageal nodose C fibers. This adds a novel mechanism of visceral afferent sensitization.
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Affiliation(s)
- Shizhong Zhang
- Division of Gastroenterology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Gintautas Grabauskas
- Division of Gastroenterology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Xiaoyin Wu
- Division of Gastroenterology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Moon Kyung Joo
- Division of Gastroenterology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Andrea Heldsinger
- Division of Gastroenterology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Il Song
- Division of Gastroenterology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Chung Owyang
- Division of Gastroenterology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Shaoyong Yu
- Division of Gastroenterology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan
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Neural plasticity in the gastrointestinal tract: chronic inflammation, neurotrophic signals, and hypersensitivity. Acta Neuropathol 2013; 125:491-509. [PMID: 23417735 DOI: 10.1007/s00401-013-1099-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 01/31/2013] [Accepted: 02/07/2013] [Indexed: 12/28/2022]
Abstract
Neural plasticity is not only the adaptive response of the central nervous system to learning, structural damage or sensory deprivation, but also an increasingly recognized common feature of the gastrointestinal (GI) nervous system during pathological states. Indeed, nearly all chronic GI disorders exhibit a disease-stage-dependent, structural and functional neuroplasticity. At structural level, GI neuroplasticity usually comprises local tissue hyperinnervation (neural sprouting, neural, and ganglionic hypertrophy) next to hypoinnervated areas, a switch in the neurochemical (neurotransmitter/neuropeptide) code toward preferential expression of neuropeptides which are frequently present in nociceptive neurons (e.g., substance P/SP, calcitonin-gene-related-peptide/CGRP) and of ion channels (TRPV1, TRPA1, PAR2), and concomitant activation of peripheral neural glia. The functional counterpart of these structural alterations is altered neuronal electric activity, leading to organ dysfunction (e.g., impaired motility and secretion), together with reduced sensory thresholds, resulting in hypersensitivity and pain. The present review underlines that neural plasticity in all GI organs, starting from esophagus, stomach, small and large intestine to liver, gallbladder, and pancreas, actually exhibits common phenotypes and mechanisms. Careful appraisal of these GI neuroplastic alterations reveals that--no matter which etiology, i.e., inflammatory, infectious, neoplastic/malignant, or degenerative--neural plasticity in the GI tract primarily occurs in the presence of chronic tissue- and neuro-inflammation. It seems that studying the abundant trophic and activating signals which are generated during this neuro-immune-crosstalk represents the key to understand the remarkable neuroplasticity of the GI tract.
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The transient receptor potential channel TRPA1: from gene to pathophysiology. Pflugers Arch 2012; 464:425-58. [DOI: 10.1007/s00424-012-1158-z] [Citation(s) in RCA: 262] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Revised: 09/06/2012] [Accepted: 09/06/2012] [Indexed: 12/13/2022]
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Anand P, Singh B, Jaggi AS, Singh N. Mast cells: an expanding pathophysiological role from allergy to other disorders. Naunyn Schmiedebergs Arch Pharmacol 2012; 385:657-70. [PMID: 22562473 DOI: 10.1007/s00210-012-0757-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2011] [Accepted: 04/17/2012] [Indexed: 12/16/2022]
Abstract
The mast cells are multi-effector cells with wide distribution in the different body parts and traditionally their role has been well-defined in the development of IgE-mediated hypersensitivity reactions including bronchial asthma. Due to the availability of genetically modified mast cell-deficient mice, the broadened pathophysiological role of mast cells in diverse diseases has been revealed. Mast cells exert different physiological and pathophysiological roles by secreting their granular contents, including vasoactive amines, cytokines and chemokines, and various proteases, including tryptase and chymase. Furthermore, mast cells also synthesize plasma membrane-derived lipid mediators, including prostaglandins and leukotrienes, to produce diverse biological actions. The present review discusses the pathophysiological role of mast cells in different diseases, including atherosclerosis, pulmonary hypertension, ischemia-reperfusion injury, male infertility, autoimmune disorders such as rheumatoid arthritis and multiple sclerosis, bladder pain syndrome (interstitial cystitis), anxiety, Alzheimer's disease, nociception, obesity and diabetes mellitus.
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Affiliation(s)
- Preet Anand
- Department of Chemistry, Punjabi University, Patiala 147002, India
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Huang ZJ, Li HC, Cowan AA, Liu S, Zhang YK, Song XJ. Chronic compression or acute dissociation of dorsal root ganglion induces cAMP-dependent neuronal hyperexcitability through activation of PAR2. Pain 2012; 153:1426-1437. [PMID: 22541444 DOI: 10.1016/j.pain.2012.03.025] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Revised: 03/04/2012] [Accepted: 03/23/2012] [Indexed: 02/07/2023]
Abstract
Chronic compression (CCD) or dissociation of dorsal root ganglion (DRG) can induce cyclic adenosine monophosphate (cAMP)-dependent DRG neuronal hyperexcitability and behaviorally expressed hyperalgesia. Here, we report that protease-activated receptor 2 (PAR2) activation after CCD or dissociation mediates the increase of cAMP activity and protein kinase A (PKA) and cAMP-dependent hyperexcitability and hyperalgesia in rats. CCD and dissociation, as well as trypsin (a PAR2 activator) treatment, increased level of cAMP concentration, mRNA, and protein expression for PKA subunits PKA-RII and PKA-c and protein expression of PAR2, in addition to producing neuronal hyperexcitability and, in CCD rats, thermal hyperalgesia. The increased expression of PAR2 was colocalized with PKA-c subunit. A PAR2 antagonistic peptide applied before and/or during the treatment, prevented or largely diminished the increased activity of cAMP and PKA, neuronal hyperexcitability, and thermal hyperalgesia. However, posttreatment with the PAR2 antagonistic peptide failed to alter either hyperexcitability or hyperalgesia. In contrast, an adenylyl cyclase inhibitor, SQ22536, administrated after dissociation or CCD, successfully suppressed hyperexcitability and hyperalgesia, in vitro and/or in vivo. Trypsin-induced increase of the intracellular calcium [Ca(2+)](i) was prevented in CCD or dissociation DRG neurons. These alterations were further confirmed by knockdown of PAR2 with siRNA. In addition, trypsin and PAR2 agonistic peptide-induced increase of cAMP was prevented by inhibition of PKC, but not Gαs. These findings suggest that PAR2 activation is critical to induction of nerve injury-induced neuronal hyperexcitability and cAMP-PKA activation. Inhibiting PAR2 activation may be a potential target for preventing/suppressing development of neuropathic pain.
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Affiliation(s)
- Zhi-Jiang Huang
- Department of Neurobiology, Parker University Research Institute, Dallas, TX, USA Neuroscience Research Institute, Peking University, Beijing 100191, China
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42
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Yu S, Ouyang A. Effect of synthetic cationic protein on mechanoexcitability of vagal afferent nerve subtypes in guinea pig esophagus. Am J Physiol Gastrointest Liver Physiol 2011; 301:G1052-8. [PMID: 21960520 PMCID: PMC3233783 DOI: 10.1152/ajpgi.00015.2011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Eosinophilic esophagitis is characterized by increased infiltration and degranulation of eosinophils in the esophagus. Whether eosinophil-derived cationic proteins regulate esophageal sensory nerve function is still unknown. Using synthetic cationic protein to investigate such effect, we performed extracellular recordings from vagal nodose or jugular neurons in ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Nerve excitabilities were determined by comparing action potentials evoked by esophageal distensions before and after perfusion of synthetic cationic protein poly-L-lysine (PLL) with or without pretreatment with poly-L-glutamic acid (PLGA), which neutralized cationic charges of PLL. Perfusion with PLL did not evoke action potentials in esophageal nodose C fibers but increased their responses to esophageal distension. This potentiation effect lasted for 30 min after washing out of PLL. Pretreatment with PLGA significantly inhibited PLL-induced mechanohyperexcitability of esophageal nodose C fibers. In esophageal nodose Aδ fibers, perfusion with PLL did not evoke action potentials. In contrast to nodose C fibers, both the spontaneous discharges and the responses to esophageal distension in nodose Aδ fibers were decreased by perfusion with PLL, which can be restored after washing out PLL for 30-60 min. Pretreatment with PLGA attenuated PLL-induced decrease in spontaneous discharge and mechanoexcitability of esophageal nodose Aδ fibers. In esophageal jugular C fibers, PLL neither evoked action potentials nor changed their responses to esophageal distension. Collectively, these data demonstrated that synthetic cationic protein did not evoke action potential discharges of esophageal vagal afferents but had distinctive sensitization effects on their responses to esophageal distension.
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Affiliation(s)
- Shaoyong Yu
- 1Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan; and
| | - Ann Ouyang
- 2Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania
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Andrade EL, Meotti FC, Calixto JB. TRPA1 antagonists as potential analgesic drugs. Pharmacol Ther 2011; 133:189-204. [PMID: 22119554 DOI: 10.1016/j.pharmthera.2011.10.008] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Accepted: 10/29/2011] [Indexed: 12/16/2022]
Abstract
The necessity of safe and effective treatments for chronic pain has intensified the search for new analgesic drugs. In the last few years, members of a closely-related family of ion channels, called transient receptor potential (TRP) have been identified in different cell types and their functions in physiological and pathological conditions have been characterized. The transient receptor potential ankyrin 1 (TRPA1), originally called ANKTM1 (ankyrin-like with transmembrane domains protein 1), is a molecule that has been conserved in different species during evolution; TRPA1 is a cation channel that functions as a cellular sensor, detecting mechanical, chemical and thermal stimuli, being a component of neuronal, epithelial, blood and smooth muscle tissues. In mammals, TRPA1 is largely expressed in primary sensory neurons that mediate somatosensory processes and nociceptive transmission. Recent studies have described the role of TRPA1 in inflammatory and neuropathic pain. However, its participation in cold sensation has not been agreed in different studies. In this review, we focus on data that support the relevance of the activation and blockade of TRPA1 in pain transmission, as well as the mechanisms underlying its activation and modulation by exogenous and endogenous stimuli. We also discuss recent advances in the search for new analgesic medicines targeting the TRPA1 channel.
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Affiliation(s)
- E L Andrade
- Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil
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Abstract
Despite significant progress in our understanding of the cellular and molecular mechanisms underlying sensory transduction and nociception, clinical pain management remains a considerable challenge in health care and basic research. The identification of the superfamily of transient receptor potential (TRP) cation channels, particularly TRPV1 and TRPA1, has shed light on the molecular basis of pain signaling during inflammatory conditions. TRPV1 and TRPA1 are considered as potential targets in the treatment of inflammatory pain because of their ability to be activated by nociceptive signals and sensitized by pro-inflammatory mediators. Notably, TRPA1 is expressed in visceral afferent neurons and is known to participate in inflammatory responses and the establishment of hypersensitivity. This review summarizes the current knowledge of the role of TRPA1 in sensory transduction, particularly in the context of visceral inflammation and pain in the gastrointestinal and urinary tracts.
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45
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Rothmeier AS, Ruf W. Protease-activated receptor 2 signaling in inflammation. Semin Immunopathol 2011; 34:133-49. [PMID: 21971685 DOI: 10.1007/s00281-011-0289-1] [Citation(s) in RCA: 229] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2011] [Accepted: 09/05/2011] [Indexed: 12/17/2022]
Abstract
Protease-activated receptors (PARs) are G protein-coupled receptors that are activated by proteolytical cleavage of the amino-terminus and thereby act as sensors for extracellular proteases. While coagulation proteases activate PARs to regulate hemostasis, thrombosis, and cardiovascular function, PAR2 is also activated in extravascular locations by a broad array of serine proteases, including trypsin, tissue kallikreins, coagulation factors VIIa and Xa, mast cell tryptase, and transmembrane serine proteases. Administration of PAR2-specific agonistic and antagonistic peptides, as well as studies in PAR2 knockout mice, identified critical functions of PAR2 in development, inflammation, immunity, and angiogenesis. Here, we review these roles of PAR2 with an emphasis on the role of coagulation and other extracellular protease pathways that cleave PAR2 in epithelial, immune, and neuronal cells to regulate physiological and pathophysiological processes.
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Affiliation(s)
- Andrea S Rothmeier
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
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46
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Garrison SR, Stucky CL. The dynamic TRPA1 channel: a suitable pharmacological pain target? Curr Pharm Biotechnol 2011; 12:1689-97. [PMID: 21466445 PMCID: PMC3884818 DOI: 10.2174/138920111798357302] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2010] [Accepted: 07/02/2010] [Indexed: 01/13/2023]
Abstract
Acute pain detection is vital to navigate and survive in one's environment. Protection and preservation occur because primary afferent nociceptors transduce adverse environmental stimuli into electrical impulses that are transmitted to and interpreted within high levels of the central nervous system. Therefore, it is critical that the molecular mechanisms that convert noxious information into neural signals be identified, and their specific functional roles delineated in both acute and chronic pain settings. The Transient Receptor Potential (TRP) channel family member TRP ankyrin 1 (TRPA1) is an excellent candidate molecule to explore and intricately understand how single channel properties can tailor behavioral nociceptive responses. TRPA1 appears to dynamically respond to an amazingly wide range of diverse stimuli that include apparently unrelated modalities such as mechanical, chemical and thermal stimuli that activate somatosensory neurons. How such dissimilar stimuli activate TRPA1, yet result in modality-specific signals to the CNS is unclear. Furthermore, TRPA1 is also involved in persistent to chronic painful states such as inflammation, neuropathic pain, diabetes, fibromyalgia, bronchitis and emphysema. Yet how TRPA1's role changes from an acute sensor of physical stimuli to its contribution to these diseases that are concomitant with implacable, chronic pain is unknown. TRPA1's involvement in the nociceptive machinery that relays the adverse stimuli during painful disease states is of considerable interest for drug delivery and design by many pharmaceutical entities. In this review, we will assess the current knowledge base of TRPA1 in acute nociception and persistent inflammatory pain states, and explore its potential as a therapeutic pharmacological target in chronic pervasive conditions such neuropathic pain, persistent inflammation and diabetes.
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Affiliation(s)
- Sheldon R. Garrison
- Department of Cell Biology, Neurobiology and Anatomy; 8701 Watertown Plank Road, Medical College of Wisconsin, Milwaukee, WI 53226
| | - Cheryl L. Stucky
- Department of Cell Biology, Neurobiology and Anatomy; 8701 Watertown Plank Road, Medical College of Wisconsin, Milwaukee, WI 53226
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47
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Brozmanova M, Ru F, Surdenikova L, Mazurova L, Taylor-Clark T, Kollarik M. Preferential activation of the vagal nodose nociceptive subtype by TRPA1 agonists in the guinea pig esophagus. Neurogastroenterol Motil 2011; 23:e437-45. [PMID: 21883700 PMCID: PMC3175634 DOI: 10.1111/j.1365-2982.2011.01768.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND The TRPA1 receptor is directly activated by a wide range of chemicals including many endogenous molecules relevant for esophageal pathophysiology. We addressed the hypothesis that the TRPA1 agonists differentially activate esophageal nociceptive subtypes depending on their embryological source (neural crest or epibranchial placodes). METHODS Single cell RT-PCR and whole cell patch clamp recordings were performed on the vagal neurons retrogradely labeled from the guinea pig esophagus. Extracellular recordings were made in the isolated innervated esophagus preparation ex vivo. KEY RESULTS Single cell RT-PCR revealed that the majority of the nodose (placodes-derived) and jugular (neural crest-derived) TRPV1-positive esophageal nociceptors express TRPA1. Single fiber recording showed that the TRPA1 agonists allyl-isothiocyanate (AITC) and cinnamaldehyde were effective in inducing robust action potential discharge in the nerve terminals of nodose nociceptors, but had far less effect in jugular nociceptors (approximately fivefold less). Higher efficacy of the TRPA1 agonists to activate nodose nociceptors was confirmed in the isolated esophagus-labeled vagal neurons in the whole cell patch clamp studies. Similarly to neural crest-derived vagal jugular nociceptors, the spinal DRG nociceptors that are also neural crest-derived were only modestly activated by allyl-isothiocyanate. CONCLUSIONS & INFERENCES We conclude that the TRPA1 agonists are substantially more effective activators of the placodes-derived than the neural crest-derived esophageal nociceptors. Our data predict that in esophageal diseases the presence of endogenous TRPA1 activators will be preferentially signaled by the vagal nodose nociceptors.
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Affiliation(s)
- M Brozmanova
- Pathophysiology, Jessenius Medical School, Comenius University, Martin, Slovakia
| | - F Ru
- Medicine, The Johns Hopkins School of Medicine, Baltimore, MD
| | - L Surdenikova
- Pathophysiology, Jessenius Medical School, Comenius University, Martin, Slovakia,Medicine, The Johns Hopkins School of Medicine, Baltimore, MD
| | - L Mazurova
- Pathophysiology, Jessenius Medical School, Comenius University, Martin, Slovakia
| | - T Taylor-Clark
- Medicine, The Johns Hopkins School of Medicine, Baltimore, MD
| | - M. Kollarik
- Medicine, The Johns Hopkins School of Medicine, Baltimore, MD
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48
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Poole DP, Pelayo JC, Cattaruzza F, Kuo YM, Gai G, Chiu JV, Bron R, Furness JB, Grady EF, Bunnett NW. Transient receptor potential ankyrin 1 is expressed by inhibitory motoneurons of the mouse intestine. Gastroenterology 2011; 141:565-75, 575.e1-4. [PMID: 21689654 DOI: 10.1053/j.gastro.2011.04.049] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2010] [Revised: 03/23/2011] [Accepted: 04/15/2011] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Transient receptor potential ankyrin (TRPA) 1, an excitatory ion channel expressed by sensory neurons, mediates somatic and visceral pain in response to direct activation or noxious mechanical stimulation. Although the intestine is routinely exposed to irritant alimentary compounds and inflammatory mediators that activate TRPA1, there is no direct evidence for functional TRPA1 receptors on enteric neurons, and the effects of TRPA1 activation on intestinal function have not been determined. We characterized expression of TRPA1 by enteric neurons and determined its involvement in the control of intestinal contractility and transit. METHODS TRPA1 expression was characterized by reverse-transcription polymerase chain reaction and immunofluorescence analyses. TRPA1 function was examined by Ca(2+) imaging and by assays of contractile activity and transit. RESULTS We detected TRPA1 messenger RNA in the mouse intestine and TRPA1 immunoreactivity in enteric neurons. The cecum and colon had immunoreactivity for neuronal TRPA1, but the duodenum did not. TRPA1 immunoreactivity was also detected in inhibitory motoneurons and descending interneurons, cholinergic neurons, and intrinsic primary afferent neurons. TRPA1 activators, including cinnamaldehyde, allyl isothiocyanate (AITC), and 4-hydroxynonenal, increased [Ca(2+)](i) in myenteric neurons. These were reduced by a TRPA1 antagonist (HC-030031) or deletion of Trpa1. TRPA1 activation inhibited contractility of the segments of colon but not stomach or small intestine of Trpa1(+/+) but not Trpa1(-/-) mice; this effect was reduced by tetrodotoxin or N(G)-nitro-l-arginine methyl ester. Administration of AITC by gavage did not alter gastric emptying or small intestinal transit, but luminal AITC inhibited colonic transit via TRPA1. CONCLUSIONS Functional TRPA1 is expressed by enteric neurons, and activation of neuronal TRPA1 inhibits spontaneous neurogenic contractions and transit of the colon.
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Affiliation(s)
- Daniel P Poole
- Center for the Neurobiology of Digestive Diseases, University of California, San Francisco, San Francisco, California, USA
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Holzer P. Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system. Pharmacol Ther 2011; 131:142-70. [PMID: 21420431 PMCID: PMC3107431 DOI: 10.1016/j.pharmthera.2011.03.006] [Citation(s) in RCA: 183] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Accepted: 03/01/2011] [Indexed: 12/12/2022]
Abstract
Approximately 20 of the 30 mammalian transient receptor potential (TRP) channel subunits are expressed by specific neurons and cells within the alimentary canal. They subserve important roles in taste, chemesthesis, mechanosensation, pain and hyperalgesia and contribute to the regulation of gastrointestinal motility, absorptive and secretory processes, blood flow, and mucosal homeostasis. In a cellular perspective, TRP channels operate either as primary detectors of chemical and physical stimuli, as secondary transducers of ionotropic or metabotropic receptors, or as ion transport channels. The polymodal sensory function of TRPA1, TRPM5, TRPM8, TRPP2, TRPV1, TRPV3 and TRPV4 enables the digestive system to survey its physical and chemical environment, which is relevant to all processes of digestion. TRPV5 and TRPV6 as well as TRPM6 and TRPM7 contribute to the absorption of Ca²⁺ and Mg²⁺, respectively. TRPM7 participates in intestinal pacemaker activity, and TRPC4 transduces muscarinic acetylcholine receptor activation to smooth muscle contraction. Changes in TRP channel expression or function are associated with a variety of diseases/disorders of the digestive system, notably gastro-esophageal reflux disease, inflammatory bowel disease, pain and hyperalgesia in heartburn, functional dyspepsia and irritable bowel syndrome, cholera, hypomagnesemia with secondary hypocalcemia, infantile hypertrophic pyloric stenosis, esophageal, gastrointestinal and pancreatic cancer, and polycystic liver disease. These implications identify TRP channels as promising drug targets for the management of a number of gastrointestinal pathologies. As a result, major efforts are put into the development of selective TRP channel agonists and antagonists and the assessment of their therapeutic potential.
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Key Words
- chemesthesis
- chemosensation
- gastrointestinal cancer
- gastrointestinal motility
- hypersensitivity
- hyperalgesia
- inflammation
- inflammatory bowel disease
- mechanosensation
- pain
- taste
- transducers
- trpa1
- trpc4
- trpc6
- trpm5
- trpm6
- trpv1
- trpv4
- trpv6
- aitc, allyl isothiocyanate
- cck, cholecystokinin
- cgrp, calcitonin gene-related peptide
- drg, dorsal root ganglion
- dss, dextran sulfate sodium
- gi, gastrointestinal
- gpcr, g protein-coupled receptor
- 5-ht, 5-hydroxytryptamine
- icc, interstitial cell of cajal
- mrna, messenger ribonucleic acid
- par, protease-activated receptor
- pkd, polycystic kidney disease
- rna, ribonucleic acid
- sirna, small interfering ribonucleic acid
- tnbs, trinitrobenzene sulfonic acid
- trp, transient receptor potential
- trpa, transient receptor potential ankyrin
- trpc, transient receptor potential canonical (or classical)
- trpm, transient receptor potential melastatin
- trpp, transient receptor potential polycystin
- trpv, transient receptor potential vanilloid
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Affiliation(s)
- Peter Holzer
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria.
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van Diest SA, Stanisor OI, Boeckxstaens GE, de Jonge WJ, van den Wijngaard RM. Relevance of mast cell-nerve interactions in intestinal nociception. Biochim Biophys Acta Mol Basis Dis 2011; 1822:74-84. [PMID: 21496484 DOI: 10.1016/j.bbadis.2011.03.019] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2011] [Revised: 03/11/2011] [Accepted: 03/30/2011] [Indexed: 01/06/2023]
Abstract
Cross-talk between the immune- and nervous-system is considered an important biological process in health and disease. Because mast cells are often strategically placed between nerves and surrounding (immune)-cells they may function as important intermediate cells. This review summarizes the current knowledge on bidirectional interaction between mast cells and nerves and its possible relevance in (inflammation-induced) increased nociception. Our main focus is on mast cell mediators involved in sensitization of TRP channels, thereby contributing to nociception, as well as neuron-released neuropeptides and their effects on mast cell activation. Furthermore we discuss mechanisms involved in physical mast cell-nerve interactions. This article is part of a Special Issue entitled: Mast cells in inflammation.
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Affiliation(s)
- Sophie A van Diest
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
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