Physiological Roles of the Rapidly Activated Delayed Rectifier K Current in Adult Mouse Heart Primary Pacemaker Activity.

Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na, K and Ca that produce SAN action potentials (AP) and 'pacemaker depolarizations' in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca-regulated mechanism based on a requirement for phasic release of Ca from intracellular stores and activation of an inward current-mediated by Na/Ca exchange; (ii) time- and voltage-dependent activation of Na or Ca currents, as well as a cyclic nucleotide-activated current, I; and/or (iii) a combination of (i) and (ii).

A computational investigation of cardiac caveolae as a source of persistent sodium current.

Recent studies of cholesterol-rich membrane microdomains, called caveolae, reveal that caveolae are reservoirs of "recruitable" sodium ion channels. Caveolar channels constitute a substantial and previously unrecognized source of sodium current in cardiac cells. In this paper we model for the first time caveolar sodium currents and their contributions to cardiac action potential morphology.

Regulation of caveolar cardiac sodium current by a single Gsalpha histidine residue.

Cardiac sodium channels (voltage-gated Na(+) channel subunit 1.5) reside in both the plasmalemma and membrane invaginations called caveolae. Opening of the caveolar neck permits resident channels to become functional.

Voltage-gated Nav channel targeting in the heart requires an ankyrin-G dependent cellular pathway.

Voltage-gated Na(v) channels are required for normal electrical activity in neurons, skeletal muscle, and cardiomyocytes. In the heart, Na(v)1.5 is the predominant Na(v) channel, and Na(v)1.

Autonomic regulation of voltage-gated cardiac ion channels.

Altering voltage-gated ion channel currents, by changing channel number or voltage-dependent kinetics, regulates the propagation of action potentials along the plasma membrane of individual cells and from one cell to its neighbors. Functional increases in the number of cardiac sodium channels (Na(V)1.5) at the myocardial sarcolemma are accomplished by the regulation of caveolae by beta adrenergically stimulated G-proteins.

Molecular determinants of intracellular pH modulation of human Kv1.4 N-type inactivation.

A-type K+ currents serve important functions in neural and cardiac physiology. The human A-type Kv1.4 channel (hKv1.

Localization of cardiac sodium channels in caveolin-rich membrane domains: regulation of sodium current amplitude.

This study demonstrates that caveolae, omega-shaped membrane invaginations, are involved in cardiac sodium channel regulation by a mechanism involving the alpha subunit of the stimulatory heterotrimeric G-protein, Galpha(s), via stimulation of the cell surface beta-adrenergic receptor. Stimulation of beta-adrenergic receptors with 10 micromol/L isoproterenol in the presence of a protein kinase A inhibitor increased the whole-cell sodium current by a "direct" cAMP-independent G-protein mechanism. The addition of antibodies against caveolin-3 to the cell's cytoplasm via the pipette solution abrogated this direct G protein-induced increase in sodium current, whereas antibodies to caveolin-1 or caveolin-2 did not.