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Modulation of voltage-gated K+ channels by the sodium channel ?1 subunit.

ABSTRACT: Voltage-gated sodium (Na(V)) and potassium (K(V)) channels are critical components of neuronal action potential generation and propagation. Here, we report that Na(V)?1 encoded by SCN1b, an integral subunit of Na(V) channels, coassembles with and modulates the biophysical properties of K(V)1 and K(V)7 channels, but not K(V)3 channels, in an isoform-specific manner. Distinct domains of Na(V)?1 are involved in modulation of the different K(V) channels. Studies with channel chimeras demonstrate that Na(V)?1-mediated changes in activation kinetics and voltage dependence of activation require interaction of Na(V)?1 with the channel's voltage-sensing domain, whereas changes in inactivation and deactivation require interaction with the channel's pore domain. A molecular model based on docking studies shows Na(V)?1 lying in the crevice between the voltage-sensing and pore domains of K(V) channels, making significant contacts with the S1 and S5 segments. Cross-modulation of Na(V) and K(V) channels by Na(V)?1 may promote diversity and flexibility in the overall control of cellular excitability and signaling.

SUBMITTER: Nguyen HM

PROVIDER: S-EPMC3494885 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other

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Modulation of voltage-gated K+ channels by the sodium channel β1 subunit.

Nguyen Hai M HM Miyazaki Haruko H Hoshi Naoto N Smith Brian J BJ Nukina Nobuyuki N Goldin Alan L AL Chandy K George KG

Proceedings of the National Academy of Sciences of the United States of America 20121022 45

Voltage-gated sodium (Na(V)) and potassium (K(V)) channels are critical components of neuronal action potential generation and propagation. Here, we report that Na(V)β1 encoded by SCN1b, an integral subunit of Na(V) channels, coassembles with and modulates the biophysical properties of K(V)1 and K(V)7 channels, but not K(V)3 channels, in an isoform-specific manner. Distinct domains of Na(V)β1 are involved in modulation of the different K(V) channels. Studies with channel chimeras demonstrate tha ...[more]

PMID: 23090990

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Project description:Voltage-dependent Na+ channel activation underlies action potential generation fundamental to cellular excitability. In skeletal and cardiac muscle this triggers contraction via ryanodine-receptor (RyR)-mediated sarcoplasmic reticular (SR) Ca2+ release. We here review potential feedback actions of intracellular [Ca2+] ([Ca2+]i) on Na+ channel activity, surveying their structural, genetic and cellular and functional implications, translating these to their possible clinical importance. In addition to phosphorylation sites, both Nav1.4 and Nav1.5 possess potentially regulatory binding sites for Ca2+ and/or the Ca2+-sensor calmodulin in their inactivating III-IV linker and C-terminal domains (CTD), where mutations are associated with a range of skeletal and cardiac muscle diseases. We summarize in vitro cell-attached patch clamp studies reporting correspondingly diverse, direct and indirect, Ca2+ effects upon maximal Nav1.4 and Nav1.5 currents (Imax) and their half-maximal voltages (V1/2) characterizing channel gating, in cellular expression systems and isolated myocytes. Interventions increasing cytoplasmic [Ca2+]i down-regulated Imax leaving V1/2 constant in native loose patch clamped, wild-type murine skeletal and cardiac myocytes. They correspondingly reduced action potential upstroke rates and conduction velocities, causing pro-arrhythmic effects in intact perfused hearts. Genetically modified murine RyR2-P2328S hearts modelling catecholaminergic polymorphic ventricular tachycardia (CPVT), recapitulated clinical ventricular and atrial pro-arrhythmic phenotypes following catecholaminergic challenge. These accompanied reductions in action potential conduction velocities. The latter were reversed by flecainide at RyR-blocking concentrations specifically in RyR2-P2328S as opposed to wild-type hearts, suggesting a basis for its recent therapeutic application in CPVT. We finally explore the relevance of these mechanisms in further genetic paradigms for commoner metabolic and structural cardiac disease.

Dataset Information

Modulation of voltage-gated K+ channels by the sodium channel ?1 subunit.

Publications

Modulation of voltage-gated K+ channels by the sodium channel β1 subunit.

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