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Yang Z, Shao X, Wu Y, Roy A, Garcia E, Farrell A, Pradhan S, Guo W, Gan H, Korkmaz Z, Adams E, Lu Y. Decoding Potassium Homeostasis in Cancer Metastasis and Drug Resistance: Insights from a Highly Selective DNAzyme-Based Intracellular K + Sensor. J Am Chem Soc 2025; 147:18074-18087. [PMID: 40367066 PMCID: PMC12120826 DOI: 10.1021/jacs.5c03781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
Potassium ions (K+) within the tumor microenvironment, along with dysregulation of K+ channels, play critical roles in supporting cancer cell survival and preventing their elimination. Directly monitoring changes in K+ homeostasis within cancer cells is invaluable for understanding these processes. However, achieving high selectivity over other biological metal ions, a detection dynamic range that aligns with intracellular K+ levels, and broad accessibility to research laboratories remain technically challenging for current K+ imaging probes. In this study, we report the in vitro selection of the first K+-specific RNA-cleaving DNAzyme and the development of a K+-specific DNAzyme fluorescent sensor with exceptional selectivity, achieving over 1000-fold selectivity against Na+ and more than 100-fold selectivity over other major biologically relevant metal ions. This sensor has an apparent dissociation constant (105 mM) that is close to the intracellular level of K+, and it has a broad detection range from 21 to 200 mM K+. Using this tool, we reveal a progressive decline in intracellular K+ levels in breast cancer cells with more advanced progression states. Moreover, we demonstrate that elevated extracellular K+ levels interfere with the efficacy of anticancer compounds like ML133 and Amiodarone, suggesting an underappreciated role of microenvironmental K+ in chemoresistance. Notably, blocking the Kir2.1 channel activity restored treatment sensitivity, presenting a potential strategy to overcome chemoresistance in aggressive cancers. These findings underscore the role of K+ homeostasis in tumor progression and support further exploration of ion-channel-targeted cancer therapies.
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Affiliation(s)
- Zhenglin Yang
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
| | - Xiangli Shao
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
| | - Yuting Wu
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
| | - Aritra Roy
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
| | - Elijah Garcia
- McKetta Department of Chemical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Annie Farrell
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
| | - Shreestika Pradhan
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
| | - Weijie Guo
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
| | - Heather Gan
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA
| | - Zeynep Korkmaz
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA
| | - Emily Adams
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
| | - Yi Lu
- Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA
- McKetta Department of Chemical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, 78712, USA
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Alam KA, Svalastoga P, Martinez A, Glennon JC, Haavik J. Potassium channels in behavioral brain disorders. Molecular mechanisms and therapeutic potential: A narrative review. Neurosci Biobehav Rev 2023; 152:105301. [PMID: 37414376 DOI: 10.1016/j.neubiorev.2023.105301] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/26/2023] [Accepted: 06/30/2023] [Indexed: 07/08/2023]
Abstract
Potassium channels (K+-channels) selectively control the passive flow of potassium ions across biological membranes and thereby also regulate membrane excitability. Genetic variants affecting many of the human K+-channels are well known causes of Mendelian disorders within cardiology, neurology, and endocrinology. K+-channels are also primary targets of many natural toxins from poisonous organisms and drugs used within cardiology and metabolism. As genetic tools are improving and larger clinical samples are being investigated, the spectrum of clinical phenotypes implicated in K+-channels dysfunction is rapidly expanding, notably within immunology, neurosciences, and metabolism. K+-channels that previously were considered to be expressed in only a few organs and to have discrete physiological functions, have recently been found in multiple tissues and with new, unexpected functions. The pleiotropic functions and patterns of expression of K+-channels may provide additional therapeutic opportunities, along with new emerging challenges from off-target effects. Here we review the functions and therapeutic potential of K+-channels, with an emphasis on the nervous system, roles in neuropsychiatric disorders and their involvement in other organ systems and diseases.
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Affiliation(s)
| | - Pernille Svalastoga
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway; Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway
| | | | - Jeffrey Colm Glennon
- Conway Institute for Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland.
| | - Jan Haavik
- Department of Biomedicine, University of Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Norway.
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Campos-Ríos A, Rueda-Ruzafa L, Lamas JA. The Relevance of GIRK Channels in Heart Function. MEMBRANES 2022; 12:1119. [PMID: 36363674 PMCID: PMC9698958 DOI: 10.3390/membranes12111119] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/06/2022] [Accepted: 11/07/2022] [Indexed: 06/16/2023]
Abstract
Among the large number of potassium-channel families implicated in the control of neuronal excitability, G-protein-gated inwardly rectifying potassium channels (GIRK/Kir3) have been found to be a main factor in heart control. These channels are activated following the modulation of G-protein-coupled receptors and, although they have been implicated in different neurological diseases in both human and animal studies of the central nervous system, the therapeutic potential of different subtypes of these channel families in cardiac conditions has remained untapped. As they have emerged as a promising potential tool to treat a variety of conditions that disrupt neuronal homeostasis, many studies have started to focus on these channels as mediators of cardiac dynamics, thus leading to research into their implication in cardiovascular conditions. Our aim is to review the latest advances in GIRK modulation in the heart and their role in the cardiovascular system.
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Affiliation(s)
- Ana Campos-Ríos
- CINBIO, Laboratory of Neuroscience, University of Vigo, 36310 Vigo, Spain
- Laboratory of Neuroscience, Galicia Sur Health Research Institute (IISGS), 15706 Vigo, Spain
| | - Lola Rueda-Ruzafa
- Department of Nursing Science, Physiotherapy and Medicine, Faculty of Health Sciences, University of Almeria, 04120 Almeria, Spain
| | - José Antonio Lamas
- CINBIO, Laboratory of Neuroscience, University of Vigo, 36310 Vigo, Spain
- Laboratory of Neuroscience, Galicia Sur Health Research Institute (IISGS), 15706 Vigo, Spain
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4
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Specificity of Ca 2+-activated K + channel modulation in atherosclerosis and aerobic exercise training. CURRENT TOPICS IN MEMBRANES 2022; 90:123-139. [PMID: 36368871 DOI: 10.1016/bs.ctm.2022.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Vascular smooth muscle cells express several isoforms of a number of classes of K+ channels. Potassium channels play critical roles in the regulation of vascular smooth muscle contraction as well as vascular smooth muscle cell proliferation or phenotypic modulation. There is ample evidence that it is Ca2+ that enables these two seemingly disparate functions to be tightly coupled both in healthy and disease processes. Because of the central position that potassium channels have in vasocontraction, vasorelaxation, membrane potential, and smooth muscle cell proliferation, these channels continue to possess the potential to serve as novel therapeutic targets in cardiovascular disease. While there are questions that remain regarding the complete interactions between K+ channels, vascular regulation, smooth muscle cell proliferation, and phenotypic modulation in physiological and pathophysiological conditions, a broad understanding of the contributions of each class of K+ channel to contractile and proliferative states of the vasculature has been reached. This brief review will discuss the current understanding of the role of K+ channels in vascular smooth muscle cells in health and disease using the porcine vascular smooth muscle cell model with particular attention to new scientific discoveries contributed by the authors regarding the effect of endurance exercise on the function of the K+ channels.
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Borrego J, Feher A, Jost N, Panyi G, Varga Z, Papp F. Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation. Pharmaceuticals (Basel) 2021; 14:1303. [PMID: 34959701 PMCID: PMC8704205 DOI: 10.3390/ph14121303] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 12/12/2022] Open
Abstract
The human voltage gated potassium channel Kv1.5 that conducts the IKur current is a key determinant of the atrial action potential. Its mutations have been linked to hereditary forms of atrial fibrillation (AF), and the channel is an attractive target for the management of AF. The development of IKur blockers to treat AF resulted in small molecule Kv1.5 inhibitors. The selectivity of the blocker for the target channel plays an important role in the potential therapeutic application of the drug candidate: the higher the selectivity, the lower the risk of side effects. In this respect, small molecule inhibitors of Kv1.5 are compromised due to their limited selectivity. A wide range of peptide toxins from venomous animals are targeting ion channels, including mammalian channels. These peptides usually have a much larger interacting surface with the ion channel compared to small molecule inhibitors and thus, generally confer higher selectivity to the peptide blockers. We found two peptides in the literature, which inhibited IKur: Ts6 and Osu1. Their affinity and selectivity for Kv1.5 can be improved by rational drug design in which their amino acid sequences could be modified in a targeted way guided by in silico docking experiments.
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Affiliation(s)
- Jesús Borrego
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary; (J.B.); (A.F.); (G.P.); (Z.V.)
| | - Adam Feher
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary; (J.B.); (A.F.); (G.P.); (Z.V.)
| | - Norbert Jost
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, 6725 Szeged, Hungary;
- Department of Pharmacology and Pharmacotherapy, Interdisciplinary Excellence Centre, University of Szeged, 6725 Szeged, Hungary
- ELKH-SZTE Research Group for Cardiovascular Pharmacology, Eötvös Loránd Research Network, 6725 Szeged, Hungary
| | - Gyorgy Panyi
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary; (J.B.); (A.F.); (G.P.); (Z.V.)
| | - Zoltan Varga
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary; (J.B.); (A.F.); (G.P.); (Z.V.)
| | - Ferenc Papp
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary; (J.B.); (A.F.); (G.P.); (Z.V.)
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Sato T, Yuki H, Honma T. Quantitative prediction of hERG inhibitory activities using support vector regression and the integrated hERG dataset in AMED cardiotoxicity database. CHEM-BIO INFORMATICS JOURNAL 2021. [DOI: 10.1273/cbij.21.70] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
| | - Hitomi Yuki
- RIKEN Center for Biosystems Dynamics Research
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Sultan A, Singh J, Howarth FC. Mechanisms underlying electro-mechanical dysfunction in the Zucker diabetic fatty rat heart: a model of obesity and type 2 diabetes. Heart Fail Rev 2021; 25:873-886. [PMID: 31654177 DOI: 10.1007/s10741-019-09872-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Diabetes mellitus (DM) is a major and worsening global health problem, currently affecting over 450 million people and reducing their quality of life. Type 2 diabetes mellitus (T2DM) accounts for more than 90% of DM and the global epidemic of obesity, which largely explains the dramatic increase in the incidence and prevalence of T2DM in the past 20 years. Obesity is a major risk factor for DM which is a major cause of morbidity and mortality in diabetic patients. The electro-mechanical function of the heart is frequently compromised in diabetic patients. The aim of this review is to discuss the pathophysiology of electro-mechanical dysfunction in the diabetic heart and in particular, the Zucker diabetic fatty (ZDF) rat heart, a well-studied model of T2DM and obesity.
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Affiliation(s)
- Ahmed Sultan
- Department of Physiology, College of Medicine & Health Sciences, UAE University, P.O. Box 17666, Al Ain, UAE
| | - Jaipaul Singh
- School of Forensic and Applied Sciences, University of Central Lancashire, Preston, Lancashire, UK
| | - Frank Christopher Howarth
- Department of Physiology, College of Medicine & Health Sciences, UAE University, P.O. Box 17666, Al Ain, UAE.
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Hekmat AS, Navabi Z, Alipanah H, Javanmardi K. Alamandine significantly reduces doxorubicin-induced cardiotoxicity in rats. Hum Exp Toxicol 2021; 40:1781-1795. [PMID: 33882726 DOI: 10.1177/09603271211010896] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Doxorubicin (DOX) is an anthracycline antibiotic. Despite its unwanted side effects, it has been successfully used in tumor therapy. Given that oxidative stress and inflammatory factors are essential to cardiotoxicity caused by DOX, we assumed that alamandine, which enhances endogenous antioxidants and has anti-inflammatory effects, may prevent DOX-induced cardiotoxicity. Rats received DOX (3.75 mg/kg) i.p on days 14, 21, 28, and 35 (total cumulative dose = 15 mg/kg) and alamandine (50 μg/kg/day) via mini-osmotic pumps for 42 days. At the end of the 42-day period, we evaluated hemodynamic parameters, electrocardiogram, cardiac troponin I (cTnI), superoxidase dismutase (SOD), total antioxidant capacity (TAC), malondialdehyde (MDA), inflammatory cytokines (tumor necrosis factor-α (TNF-α), IL-1β, NF-κB), apoptosis markers (caspase 3), and histopathology of haemotoxylin- and eosin-stained cardiac muscle fibers were evaluated. DOX significantly increased QT, corrected QT (QTc), and RR intervals. Alamandine co-therapy prevented ECG changes. Alamandine administration restored DOX-induced disruptions in the cardiac muscle architecture and vascular congestion. Alamandine co-therapy also alleviated other effects of DOX, including cardiac contractility, decreased systolic and diastolic blood pressure, and increased left ventricular end-diastolic pressure. Moreover, alamandine co-therapy substantially decreased the elevation of oxidative stress markers, inflammatory cytokines, and caspase 3 in DOX-treated rats. The results suggest that alamandine reduced DOX-induced cardiotoxicity via antioxidant, anti-inflammatory, and anti-apoptotic activities.
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Affiliation(s)
- Ava Soltani Hekmat
- Department of Physiology, Fasa University of Medical Sciences, Fasa, Iran
| | - Zahra Navabi
- Department of Physiology, Fasa University of Medical Sciences, Fasa, Iran
| | - Hiva Alipanah
- Department of Physiology, Fasa University of Medical Sciences, Fasa, Iran
| | - Kazem Javanmardi
- Department of Physiology, Fasa University of Medical Sciences, Fasa, Iran
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Wallace MJ, El Refaey M, Mesirca P, Hund TJ, Mangoni ME, Mohler PJ. Genetic Complexity of Sinoatrial Node Dysfunction. Front Genet 2021; 12:654925. [PMID: 33868385 PMCID: PMC8047474 DOI: 10.3389/fgene.2021.654925] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022] Open
Abstract
The pacemaker cells of the cardiac sinoatrial node (SAN) are essential for normal cardiac automaticity. Dysfunction in cardiac pacemaking results in human sinoatrial node dysfunction (SND). SND more generally occurs in the elderly population and is associated with impaired pacemaker function causing abnormal heart rhythm. Individuals with SND have a variety of symptoms including sinus bradycardia, sinus arrest, SAN block, bradycardia/tachycardia syndrome, and syncope. Importantly, individuals with SND report chronotropic incompetence in response to stress and/or exercise. SND may be genetic or secondary to systemic or cardiovascular conditions. Current management of patients with SND is limited to the relief of arrhythmia symptoms and pacemaker implantation if indicated. Lack of effective therapeutic measures that target the underlying causes of SND renders management of these patients challenging due to its progressive nature and has highlighted a critical need to improve our understanding of its underlying mechanistic basis of SND. This review focuses on current information on the genetics underlying SND, followed by future implications of this knowledge in the management of individuals with SND.
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Affiliation(s)
- Michael J. Wallace
- Frick Center for Heart Failure and Arrhythmia Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Mona El Refaey
- Frick Center for Heart Failure and Arrhythmia Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Pietro Mesirca
- CNRS, INSERM, Institut de Génomique Fonctionnelle, Université de Montpellier, Montpellier, France
- Laboratory of Excellence ICST, Montpellier, France
| | - Thomas J. Hund
- Frick Center for Heart Failure and Arrhythmia Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, United States
| | - Matteo E. Mangoni
- CNRS, INSERM, Institut de Génomique Fonctionnelle, Université de Montpellier, Montpellier, France
- Laboratory of Excellence ICST, Montpellier, France
| | - Peter J. Mohler
- Frick Center for Heart Failure and Arrhythmia Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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Ashton C, Rhie SK, Carmichael JD, Zada G. Role of KCNAB2 expression in modulating hormone secretion in somatotroph pituitary adenoma. J Neurosurg 2021; 134:787-793. [PMID: 32109873 DOI: 10.3171/2019.12.jns192435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 12/17/2019] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Prior profiling of the human pituitary adenoma (PA) DNA methylome showed the potassium channel subunit-encoding gene KCNAB2 to be highly differentially methylated between nonfunctional PAs (NFPAs) and growth hormone (GH)-secreting PAs, with greater KCNAB2 methylation detected in secretory PAs. KCNAB2 encodes an aldo-keto reductase that, among other things, negatively regulates members of the voltage-gated potassium channel (Kv) family. In this study, the authors aimed to determine whether modulation of Kcnab2 expression would alter GH secretion in the GH3 mammosomatotroph rat cell line. In addition, they examined whether dosing GH3 cells with the antiarrhythmic drug quinidine, a known inhibitor of Kv and voltage-gated sodium channels, would affect hormonal secretion. METHODS Previously generated RNA-seq data were reanalyzed to compare KCNAB2 expression levels in human NFPAs and GH-secreting PAs. Kcnab2 was overexpressed in GH3 cells using plasmid transfection and knocked down using shRNA, with confirmation by quantitative polymerase chain reaction (qPCR). GH concentrations in cell culture supernatants collected 24 hours after cell seeding were measured using enzyme-linked immunosorbent assay (ELISA). Separately, quinidine was administered to GH3 cells at graduated doses. GH and prolactin concentrations in supernatants collected 48 hours after quinidine treatment were measured by fluorometric immunoassay. RESULTS Modulation of expression at the transcript level in GH3 cells resulted in proportionate changes in the expression of GH mRNA and secretion of GH peptide, as confirmed by qPCR and ELISA. Specifically, partial knockdown of Kcnab2 was associated with fewer GH RNA transcripts and less GH secretion compared with controls, while augmentation of Kcnab2 expression was associated with more GH transcripts and secretion than the controls. Administration of quinidine (≥ 50 µM) reduced both GH and prolactin secretion in a dose-dependent fashion (p ≤ 0.05). CONCLUSIONS GH secretion in a somatotroph cell line is partially dependent on KCNAB2 gene expression and may be mitigated in vitro by quinidine. These results collectively suggest a potential new target and pharmacological candidate to be considered in the development of clinical therapeutics for acromegaly.
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Affiliation(s)
| | | | - John D Carmichael
- 3Medicine (Division of Endocrinology), Keck School of Medicine, University of Southern California, Los Angeles, California
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A public-private partnership to enrich the development of in silico predictive models for pharmacokinetic and cardiotoxic properties. Drug Discov Today 2021; 26:1275-1283. [PMID: 33516857 DOI: 10.1016/j.drudis.2021.01.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/21/2020] [Accepted: 01/22/2021] [Indexed: 12/12/2022]
Abstract
A novel framework for a public-private (PP) partnership was established by a national initiative of the Development of a Drug Discovery Informatics System, supported by the Japan Agency for Medical Research and Development (AMED). This informatics PP partnership consortium comprised private and public sectors. A database of pharmacokinetic (PK) and cardiotoxic properties was developed, with considerable expansion after integrating proprietary data from private-sector members. This database led to robust in silico prediction models with higher performance than those from the original database. This partnership is a unique example worldwide and could substantially strengthen drug discovery capabilities in both sectors.
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12
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Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness. Int J Mol Sci 2021; 22:ijms22031112. [PMID: 33498651 PMCID: PMC7865240 DOI: 10.3390/ijms22031112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/16/2021] [Accepted: 01/19/2021] [Indexed: 11/16/2022] Open
Abstract
KCNQ1 encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current IKs, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in KCNQ1 cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in KCNQ1 result in long QT syndrome, called Romano–Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. Here, we identified a homozygous KCNQ1 mutation, c.1892_1893insC (p.P631fs*20), in a patient with an isolated LQT syndrome (LQTS) without hearing loss. Nevertheless, the inheritance trait is autosomal recessive, with heterozygous family members being asymptomatic. The results of the electrophysiological characterization of the mutant, using voltage-clamp recordings in Xenopus laevis oocytes, are in agreement with an autosomal recessive disorder, since the IKs reduction was only observed in homomeric mutants, but not in heteromeric IKs channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant IKs channel complexes when they contain wild-type KCNQ1 subunits, as found in the heterozygous state. Action potential modellings confirmed that the recessive c.1892_1893insC LQT1 mutation only affects the APD of homozygous mutation carriers. Thus, our study provides the molecular mechanism for an atypical autosomal recessive LQT trait that lacks hearing impairment.
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13
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Ozturk N, Uslu S, Ozdemir S. Diabetes-induced changes in cardiac voltage-gated ion channels. World J Diabetes 2021; 12:1-18. [PMID: 33520105 PMCID: PMC7807254 DOI: 10.4239/wjd.v12.i1.1] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 11/05/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus affects the heart through various mechanisms such as microvascular defects, metabolic abnormalities, autonomic dysfunction and incompatible immune response. Furthermore, it can also cause functional and structural changes in the myocardium by a disease known as diabetic cardiomyopathy (DCM) in the absence of coronary artery disease. As DCM progresses it causes electrical remodeling of the heart, left ventricular dysfunction and heart failure. Electrophysiological changes in the diabetic heart contribute significantly to the incidence of arrhythmias and sudden cardiac death in diabetes mellitus patients. In recent studies, significant changes in repolarizing K+ currents, Na+ currents and L-type Ca2+ currents along with impaired Ca2+ homeostasis and defective contractile function have been identified in the diabetic heart. In addition, insulin levels and other trophic factors change significantly to maintain the ionic channel expression in diabetic patients. There are many diagnostic tools and management options for DCM, but it is difficult to detect its development and to effectively prevent its progress. In this review, diabetes-associated alterations in voltage-sensitive cardiac ion channels are comprehensively assessed to understand their potential role in the pathophysiology and pathogenesis of DCM.
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Affiliation(s)
- Nihal Ozturk
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Serkan Uslu
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
| | - Semir Ozdemir
- Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya 07058, Turkey
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Sekhar Pagadala N. Computational prediction of hERG blockers using homology modelling, molecular docking and QuaSAR studies. RESULTS IN CHEMISTRY 2021. [DOI: 10.1016/j.rechem.2021.100101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Johnson CM, Cui N, Xing H, Wu Y, Jiang C. The antitussive cloperastine improves breathing abnormalities in a Rett Syndrome mouse model by blocking presynaptic GIRK channels and enhancing GABA release. Neuropharmacology 2020; 176:108214. [PMID: 32622786 DOI: 10.1016/j.neuropharm.2020.108214] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 06/12/2020] [Accepted: 06/14/2020] [Indexed: 12/21/2022]
Abstract
Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene. One of the major RTT features is breathing dysfunction characterized by periodic hypo- and hyperventilation. The breathing disorders are associated with increased brainstem neuronal excitability, which can be alleviated with GABA agonists. Since neuronal hypoexcitability occurs in the forebrain of RTT models, it is necessary to find pharmacological agents with a relative preference to brainstem neurons. Here we show evidence for the improvement of breathing disorders of Mecp2-disrupted mice with the brainstem-acting drug cloperastine (CPS) and its likely neuronal targets. CPS is an over-the-counter cough medicine that has an inhibitory effect on brainstem neuronal networks. In Mecp2-disrupted mice, CPS (30 mg/kg, i.p.) decreased the occurrence of apneas/h and breath frequency variation. GIRK currents expressed in HEK cells were inhibited by CPS with IC50 1 μM. Whole-cell patch clamp recordings in locus coeruleus (LC) and dorsal tegmental nucleus (DTN) neurons revealed an overall inhibitory effect of CPS (10 μM) on neuronal firing activity. Such an effect was reversed by the GABAA receptor antagonist bicuculline (20 μM). Voltage clamp studies showed that CPS increased GABAergic sIPSCs in LC cells, which was blocked by the GABAB receptor antagonist phaclofen. Functional GABAergic connections of DTN neurons with LC cells were shown. These results suggest that CPS improves breathing dysfunction in Mecp2-null mice by blocking GIRK channels in synaptic terminals and enhancing GABA release.
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Affiliation(s)
- Christopher M Johnson
- Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA, 30303, USA
| | - Ningren Cui
- Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA, 30303, USA
| | - Hao Xing
- Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA, 30303, USA
| | - Yang Wu
- Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA, 30303, USA
| | - Chun Jiang
- Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA, 30303, USA.
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16
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Bhattacharyya S, Goswami DP, Sengupta A. Spatial velocity of the dynamic vectorcardiographic loop provides crucial insight in ventricular dysfunction. Med Hypotheses 2020; 135:109484. [DOI: 10.1016/j.mehy.2019.109484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/08/2019] [Indexed: 11/28/2022]
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17
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Cernuda B, Fernandes CT, Allam SM, Orzillo M, Suppa G, Chia Chang Z, Athanasopoulos D, Buraei Z. The molecular determinants of R-roscovitine block of hERG channels. PLoS One 2019; 14:e0217733. [PMID: 31479461 PMCID: PMC6719874 DOI: 10.1371/journal.pone.0217733] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 08/17/2019] [Indexed: 02/06/2023] Open
Abstract
Human ether-à-go-go-related gene (Kv11.1, or hERG) is a potassium channel that conducts the delayed rectifier potassium current (IKr) during the repolarization phase of cardiac action potentials. hERG channels have a larger pore than other K+channels and can trap many unintended drugs, often resulting in acquired LQTS (aLQTS). R-roscovitine is a cyclin-dependent kinase (CDK) inhibitor that induces apoptosis in colorectal, breast, prostate, multiple myeloma, other cancer cell lines, and tumor xenografts, in micromolar concentrations. It is well tolerated in phase II clinical trials. R-roscovitine inhibits open hERG channels but does not become trapped in the pore. Two-electrode voltage clamp recordings from Xenopus oocytes expressing wild-type (WT) or hERG pore mutant channels (T623A, S624A, Y652A, F656A) demonstrated that compared to WT hERG, T623A, Y652A, and F656A inhibition by 200 μM R-roscovitine was ~ 48%, 29%, and 73% weaker, respectively. In contrast, S624A hERG was inhibited more potently than WT hERG, with a ~ 34% stronger inhibition. These findings were further supported by the IC50 values, which were increased for T623A, Y652A and F656A (by ~5.5, 2.75, and 42 fold respectively) and reduced 1.3 fold for the S624A mutant. Our data suggest that while T623, Y652, and F656 are critical for R-roscovitine-mediated inhibition, S624 may not be. Docking studies further support our findings. Thus, R-roscovitine’s relatively unique features, coupled with its tolerance in clinical trials, could guide future drug screens.
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Affiliation(s)
- Bryan Cernuda
- Department of Biology, Pace University, New York, NY, United States of America
| | | | - Salma Mohamed Allam
- Department of Biology, Pace University, New York, NY, United States of America
| | - Matthew Orzillo
- Department of Biology, Pace University, New York, NY, United States of America
| | - Gabrielle Suppa
- Department of Biology, Pace University, New York, NY, United States of America
| | - Zuleen Chia Chang
- Department of Biology, Pace University, New York, NY, United States of America
| | | | - Zafir Buraei
- Department of Biology, Pace University, New York, NY, United States of America
- * E-mail:
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18
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Ogura K, Sato T, Yuki H, Honma T. Support Vector Machine model for hERG inhibitory activities based on the integrated hERG database using descriptor selection by NSGA-II. Sci Rep 2019; 9:12220. [PMID: 31434908 PMCID: PMC6704061 DOI: 10.1038/s41598-019-47536-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 06/24/2019] [Indexed: 11/09/2022] Open
Abstract
Assessing the hERG liability in the early stages of drug discovery programs is important. The recent increase of hERG-related information in public databases enabled various successful applications of machine learning techniques to predict hERG inhibition. However, most of these researches constructed the datasets from only one database, limiting the predictability and scope of the models. In this study, a hERG classification model was constructed using the largest dataset for hERG inhibition built by integrating multiple databases. The integrated dataset consisted of more than 291,000 structurally diverse compounds derived from ChEMBL, GOSTAR, PubChem, and hERGCentral. The prediction model was built by support vector machine (SVM) with descriptor selection based on Non-dominated Sorting Genetic Algorithm-II (NSGA-II) to optimize the descriptor set for maximum prediction performance with the minimal number of descriptors. The SVM classification model using 72 selected descriptors and ECFP_4 structural fingerprints recorded kappa statistics of 0.733 and accuracy of 0.984 for the test set, substantially outperforming the prediction performance of the current commercial applications for hERG prediction. Finally, the applicability domain of the prediction model was assessed based on the molecular similarity between the training set and test set compounds.
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Affiliation(s)
- Keiji Ogura
- RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan
| | - Tomohiro Sato
- RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan
| | - Hitomi Yuki
- RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan
| | - Teruki Honma
- RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan.
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19
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Vojdani S, Amirsalari S, Milanizadeh S, Molaei F, Ajalloueyane M, Khosravi A, Hamzehzadeh L, Ghasemi MM, Talee MR, Abbaszadegan MR. Mutation Screening of KCNQ1 and KCNE1 Genes in Iranian Patients With Jervell and Lange-Nielsen Syndrome. Fetal Pediatr Pathol 2019; 38:273-281. [PMID: 30942114 DOI: 10.1080/15513815.2019.1585500] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Background: Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive genetic disease with deafness and QT prolongation. Mutations in KCNQ1 and KCNE1 genes are a cause of JLNS. Our objective was to perform mutational analysis of the KCNQ1 and KCNE1 genes to determine the frequency of mutations in the Iranian population. Material and methods: Fourteen patients and their families were investigated. Mutational screening of the KCNQ1 and KCNE1 genes was performed by a polymerase chain reaction (PCR) followed by direct Sanger sequencing. Results: We identified two frameshift mutations in the KCNQ1 gene, including a novel mutation, c.1356 1356delG, and a known mutation, c.1534_1534delG. A common single nucleotide polymorphism (SNP), c.112G > A, was also found in KCNE1 in seven probands. Conclusion: A novel mutation in the KCNQ1 gene is described. There may be less frequency of mutations in the KCNQ1 and of KCNE1 genes in Iranian JLNS patients compared with other populations.
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Affiliation(s)
| | - Susan Amirsalari
- b New Hearing Technologies Research Center, Baqiatallah University of Medical Sciences , Tehran , Iran
| | | | - Fatemeh Molaei
- a Mashhad University of Medical Sciences , Mashhad , Iran
| | - Mohammad Ajalloueyane
- b New Hearing Technologies Research Center, Baqiatallah University of Medical Sciences , Tehran , Iran
| | - Arezoo Khosravi
- c New Hearing Technologies Research Center, Baqiatallah University of Medical Sciences , Tehran , Iran
| | | | | | | | - Mohammad Reza Abbaszadegan
- d Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences , Mashhad , Iran
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20
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Rodgers JL, Rodgers LE, Tian Z, Allen‐Gipson D, Panguluri SK. Sex differences in murine cardiac pathophysiology with hyperoxia exposure. J Cell Physiol 2018; 234:1491-1501. [DOI: 10.1002/jcp.27010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 06/22/2018] [Indexed: 11/10/2022]
Affiliation(s)
- Jennifer L. Rodgers
- Department of Pharmaceutical Sciences College of Pharmacy, University of South Florida Tampa Florida
| | - Lydia E. Rodgers
- Department of Pharmaceutical Sciences College of Pharmacy, University of South Florida Tampa Florida
| | - Zhi Tian
- Department of Pharmaceutical Sciences College of Pharmacy, University of South Florida Tampa Florida
| | - Diane Allen‐Gipson
- Department of Pharmaceutical Sciences College of Pharmacy, University of South Florida Tampa Florida
- Division of Allergy and Immunology, Department of Internal Medicine College of Medicine, University of South Florida Tampa Florida
| | - Siva K. Panguluri
- Department of Pharmaceutical Sciences College of Pharmacy, University of South Florida Tampa Florida
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21
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Edokobi N, Isom LL. Voltage-Gated Sodium Channel β1/β1B Subunits Regulate Cardiac Physiology and Pathophysiology. Front Physiol 2018; 9:351. [PMID: 29740331 PMCID: PMC5924814 DOI: 10.3389/fphys.2018.00351] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 03/20/2018] [Indexed: 12/19/2022] Open
Abstract
Cardiac myocyte contraction is initiated by a set of intricately orchestrated electrical impulses, collectively known as action potentials (APs). Voltage-gated sodium channels (NaVs) are responsible for the upstroke and propagation of APs in excitable cells, including cardiomyocytes. NaVs consist of a single, pore-forming α subunit and two different β subunits. The β subunits are multifunctional cell adhesion molecules and channel modulators that have cell type and subcellular domain specific functional effects. Variants in SCN1B, the gene encoding the Nav-β1 and -β1B subunits, are linked to atrial and ventricular arrhythmias, e.g., Brugada syndrome, as well as to the early infantile epileptic encephalopathy Dravet syndrome, all of which put patients at risk for sudden death. Evidence over the past two decades has demonstrated that Nav-β1/β1B subunits play critical roles in cardiac myocyte physiology, in which they regulate tetrodotoxin-resistant and -sensitive sodium currents, potassium currents, and calcium handling, and that Nav-β1/β1B subunit dysfunction generates substrates for arrhythmias. This review will highlight the role of Nav-β1/β1B subunits in cardiac physiology and pathophysiology.
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Affiliation(s)
| | - Lori L. Isom
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States
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22
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Yan S, Huang P, Wang Y, Zeng X, Zhang Y. The Venom of Ornithoctonus huwena affect the electrophysiological stability of neonatal rat ventricular myocytes by inhibiting sodium, potassium and calcium current. Channels (Austin) 2018. [PMID: 29532737 PMCID: PMC5972801 DOI: 10.1080/19336950.2018.1449497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Spider venoms are known to contain various toxins that are used as an effective means to capture their prey or to defend themselves against predators. An investigation of the properties of Ornithoctonus huwena (O.huwena) crude venom found that the venom can block neuromuscular transmission of isolated mouse phrenic nerve-diaphragm and sciatic nerve-sartorius preparations. However, little is known about its electrophysiological effects on cardiac myocytes. In this study, electrophysiological activities of ventricular myocytes were detected by 100 μg/mL venom of O.huwena, and whole cell patch-clamp technique was used to study the acute effects of the venom on action potential (AP), sodium current (INa), potassium currents (IKr, IKs, Ito1 and IK1) and L-type calcium current (ICaL). The results indicated that the venom prolongs APD90 in a frequency-dependent manner in isolated neonatal rat ventricular myocytes. 100 μg/mL venom inhibited 72.3 ± 3.6% INa current, 58.3 ± 4.2% summit current and 54 ± 6.1% the end current of IKr, and 65 ± 3.3% ICaL current, yet, didn't have obvious effect on IKs, Ito1 and IK1 currents. In conclusion, the O.huwena venom represented a multifaceted pharmacological profile. It contains abundant of cardiac channel antagonists and might be valuable tools for investigation of both channels and anti- arrhythmic therapy development.
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Affiliation(s)
- Sha Yan
- a Department of Dermatology, Xiangya Hospital , Central South University , Changsha , China.,b Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province , Central South University , Changsha , Hunan , China
| | - Pengfei Huang
- c The Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences , Hunan Normal University , Changsha , P. R. China.,d The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development , College of Life Sciences, Hunan Normal University , Changsha , China
| | - Ying Wang
- c The Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences , Hunan Normal University , Changsha , P. R. China.,d The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development , College of Life Sciences, Hunan Normal University , Changsha , China
| | - Xiongzhi Zeng
- c The Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences , Hunan Normal University , Changsha , P. R. China.,d The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development , College of Life Sciences, Hunan Normal University , Changsha , China
| | - Yiya Zhang
- a Department of Dermatology, Xiangya Hospital , Central South University , Changsha , China.,b Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province , Central South University , Changsha , Hunan , China.,c The Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences , Hunan Normal University , Changsha , P. R. China.,d The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development , College of Life Sciences, Hunan Normal University , Changsha , China
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23
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Jeevaratnam K, Chadda KR, Huang CLH, Camm AJ. Cardiac Potassium Channels: Physiological Insights for Targeted Therapy. J Cardiovasc Pharmacol Ther 2017; 23:119-129. [PMID: 28946759 PMCID: PMC5808825 DOI: 10.1177/1074248417729880] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential (AP) initiation, recovery, and refractoriness would contribute to an optimized approach to antiarrhythmic therapy that minimizes potential cardiac and extracardiac toxicity. Of these, K+ channels contribute numerous and diverse currents with specific actions on different phases in the time course of AP repolarization. These features and their site-specific distribution make particular K+ channel types attractive therapeutic targets for the development of pharmacological agents attempting antiarrhythmic therapy in conditions such as atrial fibrillation. However, progress in the development of such temporally and spatially selective antiarrhythmic drugs against particular ion channels has been relatively limited, particularly in view of our incomplete understanding of the complex physiological roles and interactions of the various ionic currents. This review summarizes the physiological properties of the main cardiac potassium channels and the way in which they modulate cardiac electrical activity and then critiques a number of available potential antiarrhythmic drugs directed at them.
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Affiliation(s)
- Kamalan Jeevaratnam
- 1 Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.,2 School of Medicine, Perdana University-Royal College of Surgeons Ireland, Serdang, Selangor Darul Ehsan, Malaysia
| | - Karan R Chadda
- 1 Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.,3 Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom
| | - Christopher L-H Huang
- 3 Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom.,4 Division of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
| | - A John Camm
- 5 Cardiac Clinical Academic Group, St George's Hospital Medical School, University of London, Cranmer Terrace, London, United Kingdom
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24
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Pilote S, Simard C, Drolet B. Fingolimod (Gilenya ® ) in multiple sclerosis: bradycardia, atrioventricular blocks, and mild effect on the QTc interval. Something to do with the L-type calcium channel? Fundam Clin Pharmacol 2017; 31:392-402. [PMID: 28299825 DOI: 10.1111/fcp.12284] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 03/03/2017] [Accepted: 03/13/2017] [Indexed: 11/28/2022]
Abstract
Cardiac arrhythmias and ECG abnormalities including bradycardia, prolongation of the QT interval, and atrioventricular (AV) conduction blocks have been extensively observed with fingolimod, the first marketed oral drug for treating the relapsing-remitting form of multiple sclerosis. This study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels: (i) in vitro, (ii) ex vivo, and (iii) in vivo. (i) Patch-clamp experiments in whole cell configuration were performed on Cav 1.2-transfected tsA201 cells exposed to fingolimod-phosphate 100 or 500 nmol/L (n = 27 cells, total) to measure drug effect on L-type calcium current (ICaL ). (ii) Langendorff perfusion experiments were undertaken on male Hartley guinea-pigs isolated hearts (n = 4) exposed to fingolimod 10 and 100 nmol/L to evaluate drug-induced effects on monophasic action potential duration measured at 90% repolarization (MAPD90 ). (iii) Implanted cardiac telemeters were used to record ECGs in guinea-pigs (n = 7) treated with a single dose of fingolimod 0.0625 mg/kg suspension, administered as an oral gavage. (i) In vitro cellular experiments showed that fingolimod-phosphate causes a concentration-dependent reduction in ICaL . (ii) Ex vivo Langendorff experiments revealed that fingolimod had no significant effect on MAPD90 . (iii) Fingolimod caused significant prolongations of the RR, PR, QT, and QTcF intervals in vivo. Reversible AV blocks were also observed in 7/7 animals. Fingolimod possesses ICaL -blocking properties, further contributing to its AV conduction-slowing effects. These properties are also consistent with its mitigated effect on the QT interval in humans, despite previously shown HERG-blocking effect.
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Affiliation(s)
- Sylvie Pilote
- Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), 2725, Chemin Sainte-Foy, Québec, QC, Canada, G1V 4G5
| | - Chantale Simard
- Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), 2725, Chemin Sainte-Foy, Québec, QC, Canada, G1V 4G5.,Faculté de Pharmacie, Université Laval, 1050 Avenue de la médecine, Québec, QC, Canada, G1V 0A6
| | - Benoit Drolet
- Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), 2725, Chemin Sainte-Foy, Québec, QC, Canada, G1V 4G5.,Faculté de Pharmacie, Université Laval, 1050 Avenue de la médecine, Québec, QC, Canada, G1V 0A6
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25
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Huang H, Pugsley MK, Fermini B, Curtis MJ, Koerner J, Accardi M, Authier S. Cardiac voltage-gated ion channels in safety pharmacology: Review of the landscape leading to the CiPA initiative. J Pharmacol Toxicol Methods 2017; 87:11-23. [PMID: 28408211 DOI: 10.1016/j.vascn.2017.04.002] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 03/27/2017] [Accepted: 04/06/2017] [Indexed: 12/15/2022]
Abstract
Voltage gated ion channels are central in defining the fundamental properties of the ventricular cardiac action potential (AP), and are also involved in the development of drug-induced arrhythmias. Many drugs can inhibit cardiac ion currents, including the Na+ current (INa), L-type Ca2+ current (Ica-L), and K+ currents (Ito, IK1, IKs, and IKr), and thereby affect AP properties in a manner that can trigger or sustain cardiac arrhythmias. Since publication of ICH E14 and S7B over a decade ago, there has been a focus on drug effects on QT prolongation clinically, and on the rapidly activating delayed rectifier current (IKr), nonclinically, for evaluation of proarrhythmic risk. This focus on QT interval prolongation and a single ionic current likely impacted negatively some drugs that lack proarrhythmic liability in humans. To rectify this issue, the Comprehensive in vitro proarrhythmia assay (CiPA) initiative has been proposed to integrate drug effects on multiple cardiac ionic currents with in silico modelling of human ventricular action potentials, and in vitro data obtained from human stem cell-derived ventricular cardiomyocytes to estimate proarrhythmic risk of new drugs with improved accuracy. In this review, we present the physiological functions and the molecular basis of major cardiac ion channels that contribute to the ventricle AP, and discuss the CiPA paradigm in drug development.
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Affiliation(s)
- Hai Huang
- CiToxLAB North America, 445, Armand-Frappier Boul, Laval H7V 4B3, QC, Canada
| | - Michael K Pugsley
- Department of Toxicology, Purdue Pharma L.P., Cranbury, NJ 08512, USA
| | | | - Michael J Curtis
- Cardiovascular Division, Faculty of Life Sciences & Medicine, King's College London, Rayne Institute, St Thomas' Hospital, London SE17EH, UK
| | - John Koerner
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Michael Accardi
- CiToxLAB North America, 445, Armand-Frappier Boul, Laval H7V 4B3, QC, Canada
| | - Simon Authier
- CiToxLAB North America, 445, Armand-Frappier Boul, Laval H7V 4B3, QC, Canada.
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26
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Durdagi S, Erol I, Salmas RE, Patterson M, Noskov SY. First universal pharmacophore model for hERG1 K + channel activators: acthER. J Mol Graph Model 2017; 74:153-170. [PMID: 28499268 DOI: 10.1016/j.jmgm.2017.03.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 03/28/2017] [Accepted: 03/29/2017] [Indexed: 01/31/2023]
Abstract
The intra-cavitary drug blockade of hERG1 channel has been extensively studied, both experimentally and theoretically. Structurally diverse ligands inadvertently block the hERG1 K+ channel currents lead to drug induced Long QT Syndrome (LQTS). Accordingly, designing either hERG1 channel openers or current activators, with the potential to target other binding pockets of the channel, has been introduced as a viable approach in modern anti-arrhythmia drug development. However, reports and investigations on the molecular mechanisms underlying activators binding to the hERG1 channel remain sparse and the overall molecular design principles are largely unknown. Most of the hERG1 activators were discovered during mandatory screening for hERG1 blockade. To fill this apparent deficit, the first universal pharmacophore model for hERG1 K+ channel activators was developed using PHASE. 3D structures of 18 hERG1 K+ channel activators and their corresponding measured binding affinity values were used in the development of pharmacophore models. These compounds spanned a range of structurally different chemotypes with moderate variation in binding affinity. A five sites AAHRR (A, hydrogen-bond accepting, H, hydrophobic, R, aromatic) pharmacophore model has shown reasonable high statistical results compared to the other developed more than 1000 hypotheses. This model was used to construct steric and electrostatic contour maps. The predictive power of the model was tested with 3 external test set compounds as true unknowns. Finally, the pharmacophore model was combined with the previously developed receptor-based model of hERG1 K+ channel to develop and screen novel activators. The results are quite striking and it suggests a greater future role for pharmacophore modeling and virtual drug screening simulations in deciphering complex patterns of molecular mechanisms of hERG1 channel openers at the target sites. The developed model is available upon request and it may serve as basis for the synthesis of novel therapeutic hERG1 activators.
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Affiliation(s)
- Serdar Durdagi
- Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
| | - Ismail Erol
- Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey; Department of Chemistry, Gebze Technical University, Kocaeli, Turkey
| | - Ramin Ekhteiari Salmas
- Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey
| | - Matthew Patterson
- Centre for Molecular Simulation, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Sergei Y Noskov
- Centre for Molecular Simulation, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
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27
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Du D, Yang H, Ednie AR, Bennett ES. In-Silico Modeling of the Functional Role of Reduced Sialylation in Sodium and Potassium Channel Gating of Mouse Ventricular Myocytes. IEEE J Biomed Health Inform 2017; 22:631-639. [PMID: 28182562 DOI: 10.1109/jbhi.2017.2664579] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Cardiac ion channels are highly glycosylated membrane proteins with up to 30% of the protein's mass containing glycans. Heart diseases often accompany individuals with congenital disorders of glycosylation (CDG). However, cardiac dysfunction among CDG patients is not yet fully understood. There is an urgent need to study how aberrant glycosylation impacts cardiac electrical signaling. Our previous works reported that congenitally reduced sialylation achieved through deletion of the sialyltransferase gene, ST3Gal4, leads to altered gating of voltage-gated Na+ and K+ channels ( and , respectively). However, linking the impact of reduced sialylation on ion channel gating to the action potential (AP) is difficult without performing computer experiments. Also, decomposing the sum of K+ currents is difficult because of complex structures and components of channels (e.g., , and ). In this study, we developed in-silico models to describe the functional role of reduced sialylation in both and gating and the AP using in vitro experimental data. Modeling results showed that reduced sialylation changes gating as follows: 1) The steady-state activation voltages of isoforms are shifted to a more depolarized potential. 2) Aberrant K+ currents ( and ) contribute to a prolonged AP duration, and altered Na+ current ( ) contributes to a shortened AP refractory period. This study contributes to a better understanding of the functional role of reduced sialylation in cardiac dysfunction that shows strong potential to provide new pharmaceutical targets for the treatment of CDG-related heart diseases.
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Argenziano M, Tiscornia G, Moretta R, Casal L, Potilinski C, Amorena C, Gras EG. Arrhythmogenic effect of androgens on the rat heart. J Physiol Sci 2017; 67:217-225. [PMID: 27241707 PMCID: PMC10717165 DOI: 10.1007/s12576-016-0459-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 05/06/2016] [Indexed: 01/05/2023]
Abstract
In most species androgens shorten the cardiac action potential and reduce the risk of afterdepolarizations. Despite the central role of the rat model in physiological studies, the effects of androgens on the rat heart are still inconclusive. We therefore performed electrophysiological studies on the perfused rat right ventricular free wall. We found a correlation between androgenic activity and a propensity to generate ventricular ectopic action potentials. We also found that the testosterone treatment increased action potential duration at 90 % of repolarization (APD90), while androgenic inhibition increased the time to peak and decreased APD90. We observed that the voltage-gated potassium channel Kv4.3 and the bi-directional membrane ion transporter NCX in the rat myocardium were regulated by androgenic hormones. One possible explanation for these findings is that due to the expression of specific ion channels in the rat myocardium, the action potential response to its hormonal background is different from those described in other experimental models. Our results indicate that androgenic control of NCX expression plays a key role in determining arrhythmogenicity in the rat heart.
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Affiliation(s)
- Mariana Argenziano
- Centro de Estudios en Salud y Medio Ambiente (CESyMA), Escuela de Ciencia y Tecnología (ECyT), Universidad Nacional de General San Martín (UNSAM), Av. Gral. Paz 5445, INTI, Edificio 23, 1650, San Martin, Buenos Aires, Argentina
| | - Gisela Tiscornia
- Centro de Estudios en Salud y Medio Ambiente (CESyMA), Escuela de Ciencia y Tecnología (ECyT), Universidad Nacional de General San Martín (UNSAM), Av. Gral. Paz 5445, INTI, Edificio 23, 1650, San Martin, Buenos Aires, Argentina
| | - Rosalia Moretta
- Centro de Estudios en Salud y Medio Ambiente (CESyMA), Escuela de Ciencia y Tecnología (ECyT), Universidad Nacional de General San Martín (UNSAM), Av. Gral. Paz 5445, INTI, Edificio 23, 1650, San Martin, Buenos Aires, Argentina
| | - Leonardo Casal
- Centro de Estudios en Salud y Medio Ambiente (CESyMA), Escuela de Ciencia y Tecnología (ECyT), Universidad Nacional de General San Martín (UNSAM), Av. Gral. Paz 5445, INTI, Edificio 23, 1650, San Martin, Buenos Aires, Argentina
| | - Constanza Potilinski
- Centro de Estudios en Salud y Medio Ambiente (CESyMA), Escuela de Ciencia y Tecnología (ECyT), Universidad Nacional de General San Martín (UNSAM), Av. Gral. Paz 5445, INTI, Edificio 23, 1650, San Martin, Buenos Aires, Argentina
- The National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Carlos Amorena
- Centro de Estudios en Salud y Medio Ambiente (CESyMA), Escuela de Ciencia y Tecnología (ECyT), Universidad Nacional de General San Martín (UNSAM), Av. Gral. Paz 5445, INTI, Edificio 23, 1650, San Martin, Buenos Aires, Argentina
- The National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - Eduardo Garcia Gras
- Centro de Estudios en Salud y Medio Ambiente (CESyMA), Escuela de Ciencia y Tecnología (ECyT), Universidad Nacional de General San Martín (UNSAM), Av. Gral. Paz 5445, INTI, Edificio 23, 1650, San Martin, Buenos Aires, Argentina.
- The National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina.
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George SA, Faye NR, Murillo-Berlioz A, Lee KB, Trachiotis GD, Efimov IR. At the Atrioventricular Crossroads: Dual Pathway Electrophysiology in the Atrioventricular Node and its Underlying Heterogeneities. Arrhythm Electrophysiol Rev 2017; 6:179-185. [PMID: 29326832 DOI: 10.15420/aer.2017.30.1] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The atrioventricular node (AVN) is a complex structure that performs a variety of functions in the heart. The AVN is primarily an electrical gatekeeper between the atria and ventricles and introduces a delay between atrial and ventricular excitation, allowing for efficient ventricular filling. The AVN is composed of several compartments that safely transmit electrical excitation from the atria to the ventricles via the fast or slow pathways. There are many electrophysiological differences between these pathways, including conduction time and electrical refractoriness, that increase the predisposition of the atrioventricular junction to arrhythmias such as atrioventricular nodal re-entrant tachycardia. These varied electrophysiological characteristics of the fast and slow pathways stem from their unique structural and molecular composition (tissue and cellular geometry, ion channels and gap junctions). This review summarises the structural and molecular heterogeneities of the human AVN and how they result in electrophysiological variations and arrhythmias.
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Affiliation(s)
- Sharon A George
- Department of Biomedical Engineering, The George Washington University,Washington, DC, USA
| | - N Rokhaya Faye
- Department of Biomedical Engineering, The George Washington University,Washington, DC, USA
| | - Alejandro Murillo-Berlioz
- Department of Biomedical Engineering, The George Washington University,Washington, DC, USA.,Division of Cardiothoracic Surgery and Cardiothoracic Research, Veterans Affairs Medical Center,Washington, DC, USA
| | - K Benjamin Lee
- Department of Biomedical Engineering, The George Washington University,Washington, DC, USA.,Division of Cardiothoracic Surgery and Cardiothoracic Research, Veterans Affairs Medical Center,Washington, DC, USA
| | - Gregory D Trachiotis
- Division of Cardiothoracic Surgery and Cardiothoracic Research, Veterans Affairs Medical Center,Washington, DC, USA
| | - Igor R Efimov
- Department of Biomedical Engineering, The George Washington University,Washington, DC, USA
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Benson M, Iñiguez-Lluhí JA, Martens J. Sumo Modification of Ion Channels. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 963:127-141. [PMID: 28197910 DOI: 10.1007/978-3-319-50044-7_8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recently, a role for SUMO modification outside of the nucleus has emerged. Although the number of extranuclear proteins known to be sumoylated is comparatively small, ion channels represent one important new class of these proteins. Ion channels are responsible for the control of membrane excitability and therefore are critical for fundamental physiological processes such as muscle contraction, neuronal firing, and cellular homeostasis. As such, these ion-conducting proteins are subject to precise regulation. Recently, several studies have identified sumoylation as a novel mechanism of modulating ion channel function. These studies expand the list of known functions of sumoylation and reveal that, in addition to its more established role in the regulation of nuclear proteins, this modification plays important roles at the cytoplasmic face of membranes.
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Affiliation(s)
- Mark Benson
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
| | | | - Jeffrey Martens
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
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Kamendi H, Barthlow H, Lengel D, Beaudoin ME, Snow D, Mettetal JT, Bialecki RA. Quantitative pharmacokinetic-pharmacodynamic modelling of baclofen-mediated cardiovascular effects using BP and heart rate in rats. Br J Pharmacol 2016; 173:2845-58. [PMID: 27448216 DOI: 10.1111/bph.13561] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 06/29/2016] [Accepted: 07/02/2016] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND AND PURPOSE While the molecular pathways of baclofen toxicity are understood, the relationships between baclofen-mediated perturbation of individual target organs and systems involved in cardiovascular regulation are not clear. Our aim was to use an integrative approach to measure multiple cardiovascular-relevant parameters [CV: mean arterial pressure (MAP), systolic BP, diastolic BP, pulse pressure, heart rate (HR); CNS: EEG; renal: chemistries and biomarkers of injury] in tandem with the pharmacokinetic properties of baclofen to better elucidate the site(s) of baclofen activity. EXPERIMENTAL APPROACH Han-Wistar rats were administered vehicle or ascending doses of baclofen (3, 10 and 30 mg·kg(-1) , p.o.) at 4 h intervals and baclofen-mediated changes in parameters recorded. A pharmacokinetic-pharmacodynamic model was then built by implementing an existing mathematical model of BP in rats. KEY RESULTS Final model fits resulted in reasonable parameter estimates and showed that the drug acts on multiple homeostatic processes. In addition, the models testing a single effect on HR, total peripheral resistance or stroke volume alone did not describe the data. A final population model was constructed describing the magnitude and direction of the changes in MAP and HR. CONCLUSIONS AND IMPLICATIONS The systems pharmacology model developed fits baclofen-mediated changes in MAP and HR well. The findings correlate with known mechanisms of baclofen pharmacology and suggest that similar models using limited parameter sets may be useful to predict the cardiovascular effects of other pharmacologically active substances.
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Affiliation(s)
- Harriet Kamendi
- Drug Safety and Metabolism, AstraZeneca-US, Waltham, MA, USA
| | | | - David Lengel
- Drug Safety and Metabolism, AstraZeneca-US, Waltham, MA, USA
| | | | - Debra Snow
- Drug Safety and Metabolism, AstraZeneca-US, Waltham, MA, USA
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Abstract
Multiple types of voltage-gated K(+) and non-voltage-gated K(+) currents have been distinguished in mammalian cardiac myocytes based on differences in time-dependent and voltage-dependent properties and pharmacologic sensitivities. Many of the genes encoding voltage-gated K(+) (Kv) and non-voltage-gated K(+) (Kir and K2P) channel pore-forming and accessory subunits are expressed in the heart, and a variety of approaches have been, and continue to be, used to define the molecular determinants of native cardiac K(+) channels and to explore the molecular mechanisms controlling the diversity, regulation, and remodeling of these channels in the normal and diseased myocardium.
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Affiliation(s)
- Jeanne M Nerbonne
- Department of Internal Medicine, Washington University Medical School, 660 South Euclid Avenue, Box 8086, St Louis, MO 63110, USA; Department of Developmental Biology, Washington University Medical School, St Louis, MO 63110, USA.
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Dubó S, Gallegos D, Cabrera L, Sobrevia L, Zúñiga L, González M. Cardiovascular Action of Insulin in Health and Disease: Endothelial L-Arginine Transport and Cardiac Voltage-Dependent Potassium Channels. Front Physiol 2016; 7:74. [PMID: 27014078 PMCID: PMC4791397 DOI: 10.3389/fphys.2016.00074] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/15/2016] [Indexed: 12/19/2022] Open
Abstract
Impairment of insulin signaling on diabetes mellitus has been related to cardiovascular dysfunction, heart failure, and sudden death. In human endothelium, cationic amino acid transporter 1 (hCAT-1) is related to the synthesis of nitric oxide (NO) and insulin has a vascular effect in endothelial cells through a signaling pathway that involves increases in hCAT-1 expression and L-arginine transport. This mechanism is disrupted in diabetes, a phenomenon potentiated by excessive accumulation of reactive oxygen species (ROS), which contribute to lower availability of NO and endothelial dysfunction. On the other hand, electrical remodeling in cardiomyocytes is considered a key factor in heart failure progression associated to diabetes mellitus. This generates a challenge to understand the specific role of insulin and the pathways involved in cardiac function. Studies on isolated mammalian cardiomyocytes have shown prolongated action potential in ventricular repolarization phase that produces a long QT interval, which is well explained by attenuation in the repolarizing potassium currents in cardiac ventricles. Impaired insulin signaling causes specific changes in these currents, such a decrease amplitude of the transient outward K(+) (Ito) and the ultra-rapid delayed rectifier (IKur) currents where, together, a reduction of mRNA and protein expression levels of α-subunits (Ito, fast; Kv 4.2 and IKs; Kv 1.5) or β-subunits (KChIP2 and MiRP) of K(+) channels involved in these currents in a MAPK mediated pathway process have been described. These results support the hypothesis that lack of insulin signaling can produce an abnormal repolarization in cardiomyocytes. Furthermore, the arrhythmogenic potential due to reduced Ito current can contribute to an increase in the incidence of sudden death in heart failure. This review aims to show, based on pathophysiological models, the regulatory function that would have insulin in vascular system and in cardiac electrophysiology.
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Affiliation(s)
- Sebastián Dubó
- Department of Kinesiology, Faculty of Medicine, Universidad de Concepción Concepción, Chile
| | - David Gallegos
- Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción Concepción, Chile
| | - Lissette Cabrera
- Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de ConcepciónConcepción, Chile; Department of Morphophysiology, Faculty of Medicine, Universidad Diego PortalesSantiago, Chile
| | - Luis Sobrevia
- Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynecology, Faculty of Medicine, School of Medicine, Pontificia Universidad Católica de ChileSantiago, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de SevillaSeville, Spain; Faculty of Medicine and Biomedical Sciences, University of Queensland Centre for Clinical Research (UQCCR), University of QueenslandHerston, QLD, Queensland, Australia
| | - Leandro Zúñiga
- Centro de Investigaciones Médicas, Escuela de Medicina, Universidad de Talca Talca, Chile
| | - Marcelo González
- Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, Universidad de ConcepciónConcepción, Chile; Group of Research and Innovation in Vascular Health (GRIVAS-Health)Chillán, Chile
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Tissue-specific Gene Expression in Rat Hearts and Aortas in a Model of Vascular Nitrate Tolerance. J Cardiovasc Pharmacol 2016; 65:485-93. [PMID: 25626975 DOI: 10.1097/fjc.0000000000000218] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Nitroglycerin exerts a direct myocardial anti-ischemic effect even in the state of vascular nitrate tolerance. To examine the potentially diverse molecular responses in vascular and cardiac tissues, we investigated the gene expression profile of the heart and the aorta by DNA microarray in male Wistar rats that were previously made tolerant to the vascular effects of nitroglycerin. The blood pressure-lowering effect of nitroglycerin (1-100 μg/kg) was markedly attenuated in rats pretreated for 3 days with 3 × 100 mg/kg nitroglycerin. Nitric oxide content was significantly elevated in the heart but not in the aorta of nitrate-tolerant animals, which indicated tissue-specific differences in nitroglycerin bioconversion. Of 7742 genes analyzed by DNA microarray, we found that although the expression of 25 genes changed significantly in the heart (increased: Tas2r119, Map6, Cd59, Kcnh2, Kcnh3, Senp6, Mcpt1, Tshb, Haus1, Vipr1, Lrn3, Lifr; decreased: Ihh, Fgfr1, Cryge, Krt9, Agrn, C4bpb, Fcer1a, Csf3, Hsd17b11, Hsd11b2, Ctnnbl1, Prpg1, Hsf1), only 14 genes were altered in the aorta (increased: Tas2r119, Ihh, Rrad, Npm1, Snai1; decreased: Tubb2b, Usp15, Sema6c, Wfdc2, Rps21, Ramp2, Galr1, Atxn1, Lhx1) in vascular nitrate tolerance. Quantitative reverse transcription polymerase chain reaction analysis of genes related to oxidative/nitrative/nitrosative stress also showed differential expression pattern in the heart and aorta. This is the first pharmacogenomic analysis showing that nitroglycerin treatment leading to vascular nitrate tolerance differentially impacts gene expression in vascular and cardiac tissues, which indicates different tissue-specific downstream signaling pathways.
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Chapter Five - Ubiquitination of Ion Channels and Transporters. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 141:161-223. [DOI: 10.1016/bs.pmbts.2016.02.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Luo F, Gu J, Chen L, Xu X. Molecular docking and molecular dynamics studies on the structure-activity relationship of fluoroquinolone for the HERG channel. MOLECULAR BIOSYSTEMS 2015; 10:2863-9. [PMID: 25100024 DOI: 10.1039/c4mb00396a] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Fluoroquinolones play an important role in the treatment of serious bacterial infections, but at the same time they could lead to cardiac toxicity due to the blockage of the HERG potassium channel, which even leads to the withdrawal of some fluoroquinolones. Blockage of the HERG potassium channel by drugs or drug-like compounds has become a critical problem in drug discovery. Though there were large amounts of bioactivity data of fluoroquinolones on the blockage of HERG, little structural basis of binding of blockers to the HERG channel was known. Here, we combined molecular docking, molecular dynamics simulations, free energy calculations and binding energy decomposition analysis to explore the binding modes of fluoroquinolones in the HERG potassium channel. The calculated binding free energies were consistent with the experimental binding affinities. Our results showed that the CH3 group in MX was favorable for the binding to the HERG channel, while Tyr652 and Phe656 were critical for the hydrophobic interaction between fluoroquinolones and the HERG channel. We expected that our results of calculation could provide important insights for the rational design and discovery of drugs.
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Affiliation(s)
- Fang Luo
- Beijing National Laboratory for Molecular Sciences, State Key Lab of Rare Earth Material Chemistry and Applications, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China.
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Dell’Era P, Benzoni P, Crescini E, Valle M, Xia E, Consiglio A, Memo M. Cardiac disease modeling using induced pluripotent stem cell-derived human cardiomyocytes. World J Stem Cells 2015; 7:329-342. [PMID: 25815118 PMCID: PMC4369490 DOI: 10.4252/wjsc.v7.i2.329] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/27/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Causative mutations and variants associated with cardiac diseases have been found in genes encoding cardiac ion channels, accessory proteins, cytoskeletal components, junctional proteins, and signaling molecules. In most cases the functional evaluation of the genetic alteration has been carried out by expressing the mutated proteins in in-vitro heterologous systems. While these studies have provided a wealth of functional details that have greatly enhanced the understanding of the pathological mechanisms, it has always been clear that heterologous expression of the mutant protein bears the intrinsic limitation of the lack of a proper intracellular environment and the lack of pathological remodeling. The results obtained from the application of the next generation sequencing technique to patients suffering from cardiac diseases have identified several loci, mostly in non-coding DNA regions, which still await functional analysis. The isolation and culture of human embryonic stem cells has initially provided a constant source of cells from which cardiomyocytes (CMs) can be obtained by differentiation. Furthermore, the possibility to reprogram cellular fate to a pluripotent state, has opened this process to the study of genetic diseases. Thus induced pluripotent stem cells (iPSCs) represent a completely new cellular model that overcomes the limitations of heterologous studies. Importantly, due to the possibility to keep spontaneously beating CMs in culture for several months, during which they show a certain degree of maturation/aging, this approach will also provide a system in which to address the effect of long-term expression of the mutated proteins or any other DNA mutation, in terms of electrophysiological remodeling. Moreover, since iPSC preserve the entire patients’ genetic context, the system will help the physicians in identifying the most appropriate pharmacological intervention to correct the functional alteration. This article summarizes the current knowledge of cardiac genetic diseases modelled with iPSC.
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Chae YJ, Lee KJ, Lee HJ, Sung KW, Choi JS, Lee EH, Hahn SJ. Endoxifen, the active metabolite of tamoxifen, inhibits cloned hERG potassium channels. Eur J Pharmacol 2015; 752:1-7. [PMID: 25680947 DOI: 10.1016/j.ejphar.2015.01.048] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 01/15/2015] [Accepted: 01/19/2015] [Indexed: 11/27/2022]
Abstract
The effects of tamoxifen, and its active metabolite endoxifen (4-hydroxy-N-desmethyl-tamoxifen), on hERG currents stably expressed in HEK cells were investigated using the whole-cell patch-clamp technique and an immunoblot assay. Tamoxifen and endoxifen inhibited hERG tail currents at -50mV in a concentration-dependent manner with IC50 values of 1.2 and 1.6μM, respectively. The steady-state activation curve of the hERG currents was shifted to the hyperpolarizing direction in the presence of endoxifen. The voltage-dependent inhibition of hERG currents by endoxifen increased steeply in the voltage range of channel activation. The inhibition by endoxifen displayed a shallow voltage dependence (δ=0.18) in the full activation voltage range. A fast application of endoxifen induced a reversible block of hERG tail currents during repolarization in a concentration-dependent manner, which suggested an interaction with the open state of the channel. Endoxifen also decreased the hERG current elicited by a 5s depolarizing pulse to +60mV to inactivate the hERG currents, suggesting an interaction with the activated (open and/or inactivated) states of the channels. Tamoxifen and endoxifen inhibited the hERG channel protein trafficking to the plasma membrane in a concentration-dependent manner with endoxifen being more potent than tamoxifen. These results indicated that tamoxifen and endoxifen inhibited the hERG current by direct channel blockage and by the disruption of channel trafficking to the plasma membrane in a concentration-dependent manner. A therapeutic concentration of endoxifen inhibited the hERG current by preferentially interacting with the activated (open and/or inactivated) states of the channel.
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Affiliation(s)
- Yun Ju Chae
- Department of Physiology, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Keon Jin Lee
- Department of Physiology, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Hong Joon Lee
- Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Ki-Wug Sung
- Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Jin-Sung Choi
- College of Pharmacy, Integrated Research Institute of Pharmaceutical, The Catholic University of Korea, Gyeonggi-do, Republic of Korea
| | - Eun Hui Lee
- Department of Physiology, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Sang June Hahn
- Department of Physiology, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
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Pugsley MK, Curtis MJ, Hayes ES. Biophysics and Molecular Biology of Cardiac Ion Channels for the Safety Pharmacologist. Handb Exp Pharmacol 2015; 229:149-203. [PMID: 26091640 DOI: 10.1007/978-3-662-46943-9_7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Cardiac safety pharmacology is a continuously evolving discipline that uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment of a new chemical entity (NCE). The aim of cardiac safety pharmacology is to characterise the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug's adverse effects on the heart using continuously evolving methodology. Unlike Toxicology, safety pharmacology includes within its remit a regulatory requirement to predict the risk of rare cardiotoxic (potentially lethal) events such as torsades de pointes (TdP), which is statistically associated with drug-induced changes in the QT interval of the ECG due to blockade of I Kr or K v11.1 current encoded by hERG. This gives safety pharmacology its unique character. The key issues for the safety pharmacology assessment of a drug on the heart are detection of an adverse effect liability, projection of the data into safety margin calculation and clinical safety monitoring. This chapter will briefly review the current cardiac safety pharmacology paradigm outlined in the ICH S7A and ICH S7B guidance documents and the non-clinical models and methods used in the evaluation of new chemical entities in order to define the integrated risk assessment for submission to regulatory authorities. An overview of how the present cardiac paradigm was developed will be discussed, explaining how it was based upon marketing authorisation withdrawal of many non-cardiovascular compounds due to unanticipated proarrhythmic effects. The role of related biomarkers (of cardiac repolarisation, e.g. prolongation of the QT interval of the ECG) will be considered. We will also provide an overview of the 'non-hERG-centric' concepts utilised in the evolving comprehensive in vitro proarrhythmia assay (CIPA) that details conduct of the proposed ion channel battery test, use of human stem cells and application of in silico models to early cardiac safety assessment. The summary of our current understanding of the triggers of TdP will include the interplay between action potential (AP) prolongation, early and delayed afterdepolarisation and substrates for re-entry arrhythmias.
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Affiliation(s)
- Michael K Pugsley
- Global Safety Pharmacology and Toxicology/Pathology, Janssen Pharmaceuticals LLC, 1000 Route 202 South, Raritan, NJ, 08869, USA,
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Chae YJ, Lee HJ, Jeon JH, Kim IB, Choi JS, Sung KW, Hahn SJ. Effects of donepezil on hERG potassium channels. Brain Res 2014; 1597:77-85. [PMID: 25498859 DOI: 10.1016/j.brainres.2014.11.057] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 11/04/2014] [Accepted: 11/27/2014] [Indexed: 11/26/2022]
Abstract
Donepezil is a potent, selective inhibitor of acetylcholinesterase, which is used for the treatment of Alzheimer's disease. Whole-cell patch-clamp technique and Western blot analyses were used to study the effects of donepezil on the human ether-a-go-go-related gene (hERG) channel. Donepezil inhibited the tail current of the hERG in a concentration-dependent manner with an IC50 of 1.3 μM. The metabolites of donepezil, 6-ODD and 5-ODD, inhibited the hERG currents in a similar concentration-dependent manner; the IC50 values were 1.0 and 1.5 μM, respectively. A fast drug perfusion system demonstrated that donepezil interacted with both the open and inactivated states of the hERG. A fast application of donepezil during the tail currents inhibited the open state of the hERG in a concentration-dependent manner with an IC50 of 2.7 μM. Kinetic analysis of donepezil in an open state of the hERG yielded blocking and unblocking rate constants of 0.54 µM(-1)s(-1) and 1.82 s(-1), respectively. The block of the hERG by donepezil was voltage-dependent with a steep increase across the voltage range of channel activation. Donepezil caused a reduction in the hERG channel protein trafficking to the plasma membrane at low concentration, but decreased the channel protein expression at higher concentrations. These results suggest that donepezil inhibited the hERG at a supratherapeutic concentration, and that it did so by preferentially binding to the activated (open and/or inactivated) states of the channels and by inhibiting the trafficking and expression of the hERG channel protein in the plasma membrane.
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Affiliation(s)
- Yun Ju Chae
- Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, 222 Banpo-daero, Seocho-gu, Korea
| | - Hong Joon Lee
- Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
| | - Ji Hyun Jeon
- Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
| | - In-Beom Kim
- Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
| | - Jin-Sung Choi
- College of Pharmacy, Integrated Research Institute of Pharmaceutical, The Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon, Gyeonggi-do, Korea
| | - Ki-Wug Sung
- Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
| | - Sang June Hahn
- Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, 222 Banpo-daero, Seocho-gu, Korea.
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Abstract
INTRODUCTION Cardiac K(+) channels play a critical role in maintaining the normal electrical activity of the heart by setting the cell resting membrane potential and by determining the shape and duration of the action potential. Drugs that block the rapid (IKr) and slow (IKs) components of the delayed rectifier K(+) current have been widely used as class III antiarrhythmic agents. In addition, drugs that selectively target the ultra-rapid delayed rectifier current (IKur) and the acetylcholine-gated inward rectifier current (IKAch) have shown efficacy in the treatment of patients with atrial fibrillation. In order to meet the future demand for new antiarrhythmic agents, novel approaches for cardiac K(+) channel drug discovery will need to be developed. Further, K(+) channel screening assays utilizing primary and stem cell-derived cardiomyocytes will be essential for evaluating the cardiotoxicity of potential drug candidates. AREAS COVERED In this review, the author provides a brief background on the structure, function and pharmacology of cardiac voltage-gated and inward rectifier K(+) channels. He then focuses on describing and evaluating current technologies, such as ion flux and membrane potential-sensitive dye assays, used for cardiac K(+) channel drug discovery. EXPERT OPINION Cardiac K(+) channels will continue to represent significant clinical targets for drug discovery. Although fluorescent high-throughput screening (HTS) assays and automated patch clamp systems will remain the workhorse technologies for identifying lead compounds, innovations in the areas of microfluidics, micropatterning and biosensor fabrication will allow further growth of technologies using primary and stem cell-derived cardiomyocytes.
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Affiliation(s)
- Kenneth B Walsh
- University of South Carolina, School of Medicine, Department of Pharmacology, Physiology and Neuroscience , Columbia, SC 29209 , USA +1 803 216 3519 ; +1 803 216 3538 ;
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Chae YJ, Kim DH, Lee HJ, Sung KW, Kwon OJ, Hahn SJ. Raloxifene inhibits cloned Kv4.3 channels in an estrogen receptor-independent manner. Pflugers Arch 2014; 467:1663-76. [PMID: 25231973 DOI: 10.1007/s00424-014-1602-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 08/25/2014] [Accepted: 08/26/2014] [Indexed: 12/16/2022]
Abstract
Raloxifene is widely used for the treatment and prevention of postmenopausal osteoporosis. We examined the effects of raloxifene on the Kv4.3 currents expressed in Chinese hamster ovary (CHO) cells using the whole-cell patch-clamp technique and on the long-term modulation of Kv4.3 messenger RNA (mRNA) by real-time PCR analysis. Raloxifene decreased the Kv4.3 currents with an IC50 of 2.0 μM and accelerated the inactivation and activation kinetics in a concentration-dependent manner. The inhibitory effects of raloxifene on Kv4.3 were time-dependent: the association and dissociation rate constants for raloxifene were 9.5 μM(-1) s(-1) and 23.0 s(-1), respectively. The inhibition by raloxifene was voltage-dependent (δ = 0.13). Raloxifene shifted the steady-state inactivation curves in a hyperpolarizing direction and accelerated the closed-state inactivation of Kv4.3. Raloxifene slowed the time course of recovery from inactivation, thus producing a use-dependent inhibition of Kv4.3. β-Estradiol and tamoxifen had little effect on Kv4.3. A preincubation of ICI 182,780, an estrogen receptor antagonist, for 1 h had no effect on the inhibitory effect of raloxifene on Kv4.3. The metabolites of raloxifene, raloxifene-4'-glucuronide and raloxifene-6'-glucuronide, had little or no effect on Kv4.3. Coexpression of KChIP2 subunits did not alter the drug potency and steady-state inactivation of Kv4.3 channels. Long-term exposure to raloxifene (24 h) significantly decreased the expression level of Kv4.3 mRNA. This effect was not abolished by the coincubation with ICI 182,780. Raloxifene inhibited Kv4.3 channels by interacting with their open state during depolarization and with the closed state at subthreshold potentials. This effect was not mediated via an estrogen receptor.
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Affiliation(s)
- Yun Ju Chae
- Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 137-701, South Korea
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Mustroph J, Maier LS, Wagner S. CaMKII regulation of cardiac K channels. Front Pharmacol 2014; 5:20. [PMID: 24600393 PMCID: PMC3930912 DOI: 10.3389/fphar.2014.00020] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 01/31/2014] [Indexed: 11/23/2022] Open
Abstract
Cardiac K channels are critical determinants of cardiac excitability. In hypertrophied and failing myocardium, alterations in the expression and activity of voltage-gated K channels are frequently observed and contribute to the increased propensity for life-threatening arrhythmias. Thus, understanding the mechanisms of disturbed K channel regulation in heart failure (HF) is of critical importance. Amongst others, Ca/calmodulin-dependent protein kinase II (CaMKII) has been identified as an important regulator of K channel activity. In human HF but also various animal models, increased CaMKII expression and activity has been linked to deteriorated contractile function and arrhythmias. This review will discuss the current knowledge about CaMKII regulation of several K channels, its influence on action potential properties, dispersion of repolarization, and arrhythmias with special focus on HF.
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Affiliation(s)
- Julian Mustroph
- Department of Cardiology, University Medical Center Göttingen Göttingen, Germany
| | - Lars S Maier
- Department of Cardiology, University Medical Center Göttingen Göttingen, Germany
| | - Stefan Wagner
- Department of Cardiology, University Medical Center Göttingen Göttingen, Germany
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Yang YS, Kim KD, Eun SY, Jung SC. Roles of somatic A-type K(+) channels in the synaptic plasticity of hippocampal neurons. Neurosci Bull 2014; 30:505-14. [PMID: 24526657 DOI: 10.1007/s12264-013-1399-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2013] [Accepted: 07/19/2013] [Indexed: 01/11/2023] Open
Abstract
In the mammalian brain, information encoding and storage have been explained by revealing the cellular and molecular mechanisms of synaptic plasticity at various levels in the central nervous system, including the hippocampus and the cerebral cortices. The modulatory mechanisms of synaptic excitability that are correlated with neuronal tasks are fundamental factors for synaptic plasticity, and they are dependent on intracellular Ca(2+)-mediated signaling. In the present review, the A-type K(+) (IA) channel, one of the voltage-dependent cation channels, is considered as a key player in the modulation of Ca(2+) influx through synaptic NMDA receptors and their correlated signaling pathways. The cellular functions of IA channels indicate that they possibly play as integral parts of synaptic and somatic complexes, completing the initiation and stabilization of memory.
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Affiliation(s)
- Yoon-Sil Yang
- Department of Physiology, School of Medicine, Jeju National University, Jeju, 690756, Republic of Korea
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Takahashi K, Naruse K. Stretch-activated BK channel and heart function. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2013; 110:239-44. [PMID: 23281538 DOI: 10.1016/j.pbiomolbio.2012.08.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The heart is an organ that is exposed to extreme dynamic mechanical stimuli. From birth till death, the heart indefinitely repeats periodic contraction and dilation, i.e., shortening and elongation of cardiomyocytes. Mechanical stretch elicits a change in heart rate and may cause arrhythmia if it is excessive. Thus, mechanosensitivity is crucial to heart function. The molecule that is substantially involved in mechanosensitivity is a stretch-activated ion channel. Among several ion channels believed to be activated by stretch in the heart, the stretch-activated KCa (SAKCA) channel, a member of the group of large conductance (Big Potassium, BK) channels, shows a mechanosensitive (MS) response to membrane stretch. As BK channels respond to voltage and intracellular calcium concentration with large conductance, they are considered to be involved in repolarization after depolarization. Some BK channels are known to be activated by stretch and are expressed in a number of cells, including human osteoblasts and guinea pig intestinal neurons. The SAKCA channel was found to be sensitive to stretch in the chick heart. Given that the cardiomyocyte is unremittingly exposed to contraction and dilation and that it generates action potential and its contractility is modulated by intracellular calcium concentration, the SAKCA channel, which is dependent voltage and calcium, may be involved in action potential generation. It was recently reported that a BK channel is involved in the modulation of heart rate in the mouse. Further studies regarding the role of MS BK channels, including SAKCA, in the modulation of heart rate and contractility are expected.
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Affiliation(s)
- Ken Takahashi
- Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
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Choi SH, Lee BH, Kim HJ, Jung SW, Hwang SH, Nah SY. Differential effects of ginsenoside metabolites on slowly activating delayed rectifier K(+) and KCNQ1 K(+) channel currents. J Ginseng Res 2013; 37:324-31. [PMID: 24198658 PMCID: PMC3818959 DOI: 10.5142/jgr.2013.37.324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 05/27/2013] [Accepted: 05/27/2013] [Indexed: 11/18/2022] Open
Abstract
Channels formed by the co-assembly of the KCNQ1 subunit and the mink (KCNE1) subunit underline the slowly activating delayed rectifier K+ channels (IKs) in the heart. This K+ channel is one of the main pharmacological targets for the development of drugs against cardiovascular disease. Panax ginseng has been shown to exhibit beneficial cardiovascular effects. In a previous study, we showed that ginsenoside Rg3 activates human KCNQ1 K+ channel currents through interactions with the K318 and V319 residues. However, little is known about the effects of ginsenoside metabolites on KCNQ1 K+ alone or the KCNQ1 + KCNE1 K+ (IKs) channels. In the present study, we examined the effect of protopanaxatriol (PPT) and compound K (CK) on KCNQ1 K+ and IKs channel activity expressed in Xenopus oocytes. PPT more strongly inhibited the IKs channel currents than the currents of KCNQ1 K+ alone in concentration- and voltage-dependent manners. The IC50 values on IKs and KCNQ1 alone currents for PPT were 5.18±0.13 and 10.04±0.17 μM, respectively. PPT caused a leftward shift in the activation curve of IKs channel activity, but minimally affected KCNQ1 alone. CK exhibited slight inhibition on IKs and KCNQ1 alone K+ channel currents. These results indicate that ginsenoside metabolites show limited effects on IKs channel activity, depending on the structure of the ginsenoside metabolites.
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Affiliation(s)
- Sun-Hye Choi
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea
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Abstract
Recently, we screened several KV channels for possible dependence on plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2). The channels were expressed in tsA-201 cells and the PI(4,5)P 2 was depleted by several manipulations in whole-cell experiments with parallel measurements of channel activity. In contrast to reports on excised-patches using Xenopus laevis oocytes, we found only KV 7, but none of the other tested KV channels, to be strongly dependent on PI(4,5)P 2. We now have extended our study to KV 1.2 channels, a KV channel we had not previously tested, because a new published study on excised patches showed regulation of the voltage-dependence of activation by PI(4,5)P 2. In full agreement with those published results, we found a reduction of current amplitude by ~20% after depletion of PI(4,5)P 2 and a small left shift in the activation curve of KV 1.2 channels. We also found a small reduction of KV 11.1 (hERG) currents that was not accompanied by a gating shift. In conclusion, our whole-cell methods yield a PI(4,5)P 2-dependence of KV 1.2 currents in tsA-201 cells that is comparable to findings from excised patches of Xenopus laevis oocytes. We discuss possible physiological rationales for PI(4,5)P 2 sensitivity of some ion channels and insensitivity of others.
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Affiliation(s)
- Martin Kruse
- Department of Physiology and Biophysics; University of Washington; Seattle, WA USA
| | - Bertil Hille
- Department of Physiology and Biophysics; University of Washington; Seattle, WA USA
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McBride BF. The Emerging Role of Antiarrhythmic Compounds With Atrial Selectivity in the Management of Atrial Fibrillation. J Clin Pharmacol 2013; 49:258-67. [DOI: 10.1177/0091270008325151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Finlay HJ, Jiang J, Caringal Y, Kover A, Conder ML, Xing D, Levesque P, Harper T, Hsueh MM, Atwal K, Blanar M, Wexler R, Lloyd J. Triazolo and imidazo dihydropyrazolopyrimidine potassium channel antagonists. Bioorg Med Chem Lett 2013; 23:1743-7. [DOI: 10.1016/j.bmcl.2013.01.064] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 01/10/2013] [Accepted: 01/16/2013] [Indexed: 10/27/2022]
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