Is Modulation of Sodium-Calcium Exchange a Therapeutic Option in Heart Failure?

esides the sarcoplasmic reticulum (SR) Ca 2 -ATPase (SERCA), the sarcolemmal Na -Ca 2 exchanger (NCX) is the most important Ca 2 transport protein responsible for maintaining the Ca 2 balance of the myocyte. It catalyzes the transport of Ca 2 across the membrane in exchange for Na in a reversible manner. Its activity is called "forward" when Na is transported inward and Ca 2 outward and "reversed" when ions are transported in the opposite directions. The driving force of NCX depends on Na and Ca 2 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 Ca 2 -and Na -binding regulatory sites, which are distinct from the transport sites. Thus, Na and Ca 2 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. 2] It has become clear that disturbed excitation-contraction coupling attributable to altered SR Ca 2 accumulation significantly contributes to heart failure pathophysiology. Three major factors seem to contribute to disturbed SR Ca 2 accumulation in human heart failure: (1) increased leak of Ca 2 through ryanodine receptors, (2) reduced SERCA activity, and (3) increased transsarcolemmal elimination of Ca 2 by NCX. SR Ca 2 accumulation depends on the activity of SERCA relative to transsarcolemmal Ca 2 elimination by NCX. When protein