Cardiac sodium transport and excitation-contraction coupling

Abstract

The excitation-contraction coupling (EC-coupling) links membrane depolarization with contraction in cardiomyocytes. Ca(2+) induced opening of ryanodine receptors (RyRs) leads to Ca(2+) induced Ca(2+) release (CICR) from the sarcoplasmic reticulum (SR) into the dyadic cleft between the t-tubules and SR. Ca(2+) is removed from the cytosol by the SR Ca(2+) ATPase (SERCA2) and the Na,Ca-exchanger (NCX). The NCX connects cardiac Ca(2+) and Na(+)-transport, leading to Na(+)-dependent regulation of EC-coupling by several mechanisms of which some still lack firm experimental evidence. Firstly, NCX might contribute to CICR during an action potential (AP) as Na(+)-accumulation at the intracellular site together with depolarization will trigger reverse mode exchange bringing Ca(2+) into the dyadic cleft. The controversial issue is the nature of the compartment in which Na(+) accumulates. It seems not to be the bulk cytosol, but is it part of a widespread subsarcolemmal space, a localized microdomain ("fuzzy space"), or as we propose, a more localized "spot" to which only a few membrane proteins have shared access (nanodomains)? Also, there seems to be spots where the Na,K-pump (NKA) will cause local Na(+) depletion. Secondly, Na(+) determines the rate of cytosolic Ca(2+) removal and SR Ca(2+) load by regulating the SERCA2/NCX-balance during the decay of the Ca(2+) transient. The aim of this review is to describe available data and current concepts of Na(+)-mediated regulation of cardiac EC-coupling, with special focus on subcellular microdomains and the potential roles of Na(+) transport proteins in regulating CICR and Ca(2+) extrusion in cardiomyocytes. We propose that voltage gated Na(+) channels, NCX and the NKA α2-isoform all regulate cardiac EC-coupling through control of the "Na(+) concentration in specific subcellular nanodomains in cardiomyocytes. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes."

Keywords: Calcium; EC-coupling; Microdomains; Sodium.