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Comparative effects of H+ and Ca2+ on large-conductance Ca2+- and voltage-gated Slo1 K+ channels.

ABSTRACT: Large-conductance Ca(2+)- and voltage-gated Slo1 BK channels are allosterically activated by depolarization and intracellular ligands such as Ca(2+). Of the two high-affinity Ca(2+) sensors present in the channel, the RCK1 sensor also mediates H(+)-dependent activation of the channel. In this study, we examined the comparative mechanisms of the channel activation by Ca(2+) and H(+). Steady-state macroscopic conductance-voltage measurements as well as single-channel openings at negative voltages where voltage-sensor activation is negligible showed that at respective saturating concentrations Ca(2+) is more effective in relative stabilization of the open conformation than H(+). Calculations using the Debye-Hückel formalism suggest that small structural changes in the RCK1 sensor, on the order of few angstroms, may accompany the H(+)-mediated opening of the channel. While the efficacy of H(+) in activation of the channel is less than that of Ca(2+), H(+) more effectively accelerates the activation kinetics when examined at the concentrations equipotent on macroscopic voltage-dependent activation. The RCK1 sensor therefore is capable of transducing the nature of the bound ligand and transmits qualitatively different information to the channel's permeation gate.

SUBMITTER: Hou S

PROVIDER: S-EPMC2824562 | biostudies-literature | 2009 Jul-Aug

REPOSITORIES: biostudies-literature

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Comparative effects of H+ and Ca2+ on large-conductance Ca2+- and voltage-gated Slo1 K+ channels.

Hou Shangwei S Horrigan Frank T FT Xu Rong R Heinemann Stefan H SH Hoshi Toshinori T

Channels (Austin, Tex.) 20090717 4

Large-conductance Ca(2+)- and voltage-gated Slo1 BK channels are allosterically activated by depolarization and intracellular ligands such as Ca(2+). Of the two high-affinity Ca(2+) sensors present in the channel, the RCK1 sensor also mediates H(+)-dependent activation of the channel. In this study, we examined the comparative mechanisms of the channel activation by Ca(2+) and H(+). Steady-state macroscopic conductance-voltage measurements as well as single-channel openings at negative voltages ...[more]

PMID: 19617704

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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

Comparative effects of H+ and Ca2+ on large-conductance Ca2+- and voltage-gated Slo1 K+ channels.

Publications

Comparative effects of H+ and Ca2+ on large-conductance Ca2+- and voltage-gated Slo1 K+ channels.

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