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Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels

ATP-sensitive potassium (K(ATP)) channels link cell metabolism to membrane excitability and are involved in a wide range of physiological processes including hormone secretion, control of vascular tone, and protection of cardiac and neuronal cells against ischemic injuries. In pancreatic β-cells, K(...

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Autores principales: Martin, Gregory M., Chen, Pei-Chun, Devaraneni, Prasanna, Shyng, Show-Ling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870925/
https://www.ncbi.nlm.nih.gov/pubmed/24399968
http://dx.doi.org/10.3389/fphys.2013.00386
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author Martin, Gregory M.
Chen, Pei-Chun
Devaraneni, Prasanna
Shyng, Show-Ling
author_facet Martin, Gregory M.
Chen, Pei-Chun
Devaraneni, Prasanna
Shyng, Show-Ling
author_sort Martin, Gregory M.
collection PubMed
description ATP-sensitive potassium (K(ATP)) channels link cell metabolism to membrane excitability and are involved in a wide range of physiological processes including hormone secretion, control of vascular tone, and protection of cardiac and neuronal cells against ischemic injuries. In pancreatic β-cells, K(ATP) channels play a key role in glucose-stimulated insulin secretion, and gain or loss of channel function results in neonatal diabetes or congenital hyperinsulinism, respectively. The β-cell K(ATP) channel is formed by co-assembly of four Kir6.2 inwardly rectifying potassium channel subunits encoded by KCNJ11 and four sulfonylurea receptor 1 subunits encoded by ABCC8. Many mutations in ABCC8 or KCNJ11 cause loss of channel function, thus, congenital hyperinsulinism by hampering channel biogenesis and hence trafficking to the cell surface. The trafficking defects caused by a subset of these mutations can be corrected by sulfonylureas, K(ATP) channel antagonists that have long been used to treat type 2 diabetes. More recently, carbamazepine, an anticonvulsant that is thought to target primarily voltage-gated sodium channels has been shown to correct K(ATP) channel trafficking defects. This article reviews studies to date aimed at understanding the mechanisms by which mutations impair channel biogenesis and trafficking and the mechanisms by which pharmacological ligands overcome channel trafficking defects. Insight into channel structure-function relationships and therapeutic implications from these studies are discussed.
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spelling pubmed-38709252014-01-07 Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels Martin, Gregory M. Chen, Pei-Chun Devaraneni, Prasanna Shyng, Show-Ling Front Physiol Physiology ATP-sensitive potassium (K(ATP)) channels link cell metabolism to membrane excitability and are involved in a wide range of physiological processes including hormone secretion, control of vascular tone, and protection of cardiac and neuronal cells against ischemic injuries. In pancreatic β-cells, K(ATP) channels play a key role in glucose-stimulated insulin secretion, and gain or loss of channel function results in neonatal diabetes or congenital hyperinsulinism, respectively. The β-cell K(ATP) channel is formed by co-assembly of four Kir6.2 inwardly rectifying potassium channel subunits encoded by KCNJ11 and four sulfonylurea receptor 1 subunits encoded by ABCC8. Many mutations in ABCC8 or KCNJ11 cause loss of channel function, thus, congenital hyperinsulinism by hampering channel biogenesis and hence trafficking to the cell surface. The trafficking defects caused by a subset of these mutations can be corrected by sulfonylureas, K(ATP) channel antagonists that have long been used to treat type 2 diabetes. More recently, carbamazepine, an anticonvulsant that is thought to target primarily voltage-gated sodium channels has been shown to correct K(ATP) channel trafficking defects. This article reviews studies to date aimed at understanding the mechanisms by which mutations impair channel biogenesis and trafficking and the mechanisms by which pharmacological ligands overcome channel trafficking defects. Insight into channel structure-function relationships and therapeutic implications from these studies are discussed. Frontiers Media S.A. 2013-12-24 /pmc/articles/PMC3870925/ /pubmed/24399968 http://dx.doi.org/10.3389/fphys.2013.00386 Text en Copyright © 2013 Martin, Chen, Devaraneni and Shyng. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Martin, Gregory M.
Chen, Pei-Chun
Devaraneni, Prasanna
Shyng, Show-Ling
Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels
title Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels
title_full Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels
title_fullStr Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels
title_full_unstemmed Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels
title_short Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels
title_sort pharmacological rescue of trafficking-impaired atp-sensitive potassium channels
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870925/
https://www.ncbi.nlm.nih.gov/pubmed/24399968
http://dx.doi.org/10.3389/fphys.2013.00386
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