Is modulation of sodium-calcium exchange a therapeutic option in heart failure?

Abstract

Besides the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA), the sarcolemmal Na+-Ca2+ exchanger (NCX) is the most important Ca2+ transport protein responsible for maintaining the Ca2+ balance of the myocyte. It catalyzes the transport of Ca2+ across the membrane in exchange for Na+ in a reversible manner. Its activity is called “forward” when Na+ is transported inward and Ca2+ outward and “reversed” when ions are transported in the opposite directions. The driving force of NCX depends on Na+ and Ca2+ concentrations at either side of the plasma membrane and on the membrane potential. NCX is electrogenic and carries inward (depolarizing) current in forward mode and outward (repolarizing) current in reversed mode.1 NCX consists of 9 transmembrane helices and a large cytoplasmic loop. This loop has been shown to contain Ca2+- and Na+-binding regulatory sites, which are distinct from the transport sites. Thus, Na+ and Ca2+ ions are both transport substrates and modulators of activity. At the N-terminal end of the cytoplasmic loop near the membrane-lipid interface, there is a 20-amino acid segment, designated the endogenous XIP region. This region is considered to function as an autoinhibitory domain that plays a central role in NCX regulation. In addition, PIP2, protons, ATP, and PKC-dependent effects regulate NCX activity.1–3 More recently, it was shown that the Ca2+ binding protein sorcin exerts stimulatory actions on NCX.4 Altered expression and activity of the sarcolemmal NCX may play a key role for disturbed contractile function and arrhythmogenesis in hypertrophy and heart failure. It has become clear that disturbed excitation-contraction coupling attributable to altered SR Ca2+ accumulation significantly contributes to heart failure pathophysiology.3 Three major factors seem to contribute to disturbed SR …