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Opening and closing of KCNKO potassium leak channels is tightly regulated.

ABSTRACT: Potassium-selective leak channels control neuromuscular function through effects on membrane excitability. Nonetheless, their existence as independent molecular entities was established only recently with the cloning of KCNKO from Drosophila melanogaster. Here, the operating mechanism of these 2 P domain leak channels is delineated. Single KCNKO channels switch between two long-lived states (one open and one closed) in a tenaciously regulated fashion. Activation can increase the open probability to approximately 1, and inhibition can reduce it to approximately 0.05. Gating is dictated by a 700-residue carboxy-terminal tail that controls the closed state dwell time but does not form a channel gate; its deletion (to produce a 300-residue subunit with two P domains and four transmembrane segments) yields unregulated leak channels that enter, but do not maintain, the closed state. The tail integrates simultaneous input from multiple regulatory pathways acting via protein kinases C, A, and G.

SUBMITTER: Zilberberg N

PROVIDER: S-EPMC2229483 | biostudies-other | 2000 Nov

REPOSITORIES: biostudies-other

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Opening and closing of KCNKO potassium leak channels is tightly regulated.

Zilberberg N N Ilan N N Gonzalez-Colaso R R Goldstein S A SA

The Journal of general physiology 20001101 5

Potassium-selective leak channels control neuromuscular function through effects on membrane excitability. Nonetheless, their existence as independent molecular entities was established only recently with the cloning of KCNKO from Drosophila melanogaster. Here, the operating mechanism of these 2 P domain leak channels is delineated. Single KCNKO channels switch between two long-lived states (one open and one closed) in a tenaciously regulated fashion. Activation can increase the open probability ...[more]

PMID: 11055999

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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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Opening and closing of KCNKO potassium leak channels is tightly regulated.

Publications

Opening and closing of KCNKO potassium leak channels is tightly regulated.

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