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Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures.

ABSTRACT: ATP-sensitive potassium (K_ATP) channels are uniquely evolved protein complexes that couple cell energy levels to cell excitability. They govern a wide range of physiological processes including hormone secretion, neuronal transmission, vascular dilation, and cardiac and neuronal preconditioning against ischemic injuries. In pancreatic ?-cells, K_ATP channels composed of Kir6.2 and SUR1, encoded by KCNJ11 and ABCC8, respectively, play a key role in coupling blood glucose concentration to insulin secretion. Mutations in ABCC8 or KCNJ11 that diminish channel function result in congenital hyperinsulinism. Many of these mutations principally hamper channel biogenesis and hence trafficking to the cell surface. Several small molecules have been shown to correct channel biogenesis and trafficking defects. Here, we review studies aimed at understanding how mutations impair channel biogenesis and trafficking and how pharmacological ligands overcome channel trafficking defects, particularly highlighting recent cryo-EM structural studies which have shed light on the mechanisms of channel assembly and pharmacological chaperones.

SUBMITTER: Martin GM

PROVIDER: S-EPMC6994177 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures.

Martin Gregory M GM Sung Min Woo MW Shyng Show-Ling SL

Molecular and cellular endocrinology 20191209

ATP-sensitive potassium (K<sub>ATP</sub>) channels are uniquely evolved protein complexes that couple cell energy levels to cell excitability. They govern a wide range of physiological processes including hormone secretion, neuronal transmission, vascular dilation, and cardiac and neuronal preconditioning against ischemic injuries. In pancreatic β-cells, K<sub>ATP</sub> channels composed of Kir6.2 and SUR1, encoded by KCNJ11 and ABCC8, respectively, play a key role in coupling blood glucose conc ...[more]

PMID: 31821855

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Project description:ATP-sensitive potassium channels (KATP channels) are hetero-octameric nucleotide-gated ion channels that couple cellular metabolism to excitability in various tissues. In the heart, KATP channels are activated during ischaemia and potentially during adrenergic stimulation. In the vasculature, they are normally active at a low level, reducing vascular tone, but the ubiquitous nature of these channels leads to complex and poorly understood channelopathies as a result of gain- or loss-of-function mutations. Zebrafish (ZF) models of these channelopathies may provide insights to the link between molecular dysfunction and complex pathophysiology, but this requires understanding the tissue dependence of channel activity and subunit specificity. Thus far, direct analysis of ZF KATP expression and functional properties has only been performed in pancreatic β-cells. Using a comprehensive combination of genetically modified fish, electrophysiology and gene expression analysis, we demonstrate that ZF cardiac myocytes (CM) and vascular smooth muscle (VSM) express functional KATP channels of similar subunit composition, structure and metabolic sensitivity to their mammalian counterparts. However, in contrast to mammalian cardiovascular KATP channels, ZF channels are insensitive to potassium channel opener drugs (pinacidil, minoxidil) in both chambers of the heart and in VSM. The results provide a first characterization of the molecular properties of fish KATP channels and validate the use of such genetically modified fish as models of human Cantú syndrome and ABCC9-related Intellectual Disability and Myopathy syndrome. KEY POINTS: Zebrafish cardiac myocytes (CM) and vascular smooth muscle (VSM) express functional KATP channels of similar subunit composition, structure and metabolic sensitivity to their mammalian counterparts. In contrast to mammalian cardiovascular KATP channels, zebrafish channels are insensitive to potassium channel opener drugs (pinacidil, minoxidil) in both chambers of the heart and in VSM. We provide a first characterization of the molecular properties of fish KATP channels and validate the use of such genetically modified fish as models of human Cantú syndrome and ABCC9-related Intellectual Disability and Myopathy syndrome.

Project description:BackgroundHypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (KATP) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of KATP pore-forming subunits.MethodsWhole heart KATP RNA expression was probed. Whole-cell KATP current and action potentials were recorded in isolated wild-type (WT), Kir6.1 global knockout (6.1-gKO), and Kir6.2 global knockout (6.2-gKO) murine atrial myocytes. Langendorff-perfused hearts were assessed for atrial effective refractory period (ERP), conduction velocity, wavefront path length (WFPL), and arrhymogenicity under normoxia/hypoxia using a microelectrode array and programmed electrical stimulation. Heart histology was assessed.ResultsExpression patterns were essentially identical for all KATP subunit RNA across human heart, whereas in mouse, Kir6.1 and SUR2 (sulphonylurea receptor subunit) were higher in ventricle than atrium, and Kir6.2 and SUR1 were higher in atrium. Compared with WT, 6.2-gKO atrial myocytes had reduced tolbutamide-sensitive current and action potentials were more depolarized with slower upstroke and reduced peak amplitude. Action potential duration was prolonged in 6.1-gKO atrial myocytes, absent of changes in other ion channel gene expression or atrial myocyte hypertrophy. In Langendorff-perfused hearts, baseline atrial ERP was prolonged and conduction velocity reduced in both KATP knockout mice compared with WT, without histological fibrosis. Compared with baseline, hypoxia led to conduction velocity slowing, stable ERP, and WFPL shortening in WT and 6.1-gKO hearts, whereas WFPL was stable in 6.2-gKO hearts due to ERP prolongation with conduction velocity slowing. Tolbutamide reversed hypoxia-induced WFPL shortening in WT and 6.1-gKO hearts through ERP prolongation. Atrial tachyarrhythmias inducible with programmed electrical stimulation during hypoxia in WT and 6.1-gKO mice correlated with WFPL shortening. Spontaneous arrhythmia was not seen.ConclusionsKATP block/absence leads to cellular and tissue level atrial electrophysiological modification. Kir6.2 global knockout prevents hypoxia-induced atrial WFPL shortening and atrial arrhythmogenicity to programmed electrical stimulation. This mechanism could be explored translationally to treat ischemically driven atrial arrhythmia.

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Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures.

Publications

Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures.

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