Cardiac sodium transport and excitation-contraction coupling

The excitation-contraction coupling (EC-coupling) links membrane depolarization with contraction in cardiomyocytes. Ca2+ induced opening of ryanodine receptors (RyRs) leads to Ca2+ induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) into the dyadic cleft between the t-tubules and SR. Ca2+ is removed from the cytosol by the SR Ca2+ ATPase (SERCA2) and the Na,Ca-exchanger (NCX). The NCX connects cardiac Ca2+ 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 Ca2+ 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 Ca2+ removal and SR Ca2+ load by regulating the SERCA2/NCX-balance during the decay of the Ca2+ 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 Ca2+ extrusion in cardiomyocytes. We propose that voltage gated Na+ channels, NCX and the NKA alpha 2-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. (C) 2013 Elsevier Ltd. All rights reserved.