Na+ transport in cardiac myocytes; Implications for excitation-contraction coupling

Abstract

Intracellular Na(+) concentration ([Na(+)](i)) is very important in modulating the contractile and electrical activity of the heart. Upon electrical excitation of the myocardium, voltage-dependent Na(+) channels open, triggering the upstroke of the action potential (AP). During the AP, Ca(2+) enters the myocytes via L-type Ca(2+) channels. This triggers Ca(2+) release from the sarcoplasmic reticulum (SR) and thus activates contraction. Relaxation occurs when cytosolic Ca(2+) declines, mainly due to re-uptake into the SR via SR Ca(2+)-ATPase and extrusion from the cell via the Na(+)/Ca(2+) exchanger (NCX). NCX extrudes one Ca(2+) ion in exchange for three Na(+) ions and its activity is critically regulated by [Na(+)](i). Thus, via NCX, [Na(+)](i) is centrally involved in the regulation of intracellular [Ca(2+)] and contractility. Na(+) brought in by Na(+) channels, NCX and other Na(+) entry pathways is extruded by the Na(+)/K(+) pump (NKA) to keep [Na(+)](i) low. NKA is regulated by phospholemman, a small sarcolemmal protein that associates with NKA. Unphosphorylated phospholemman inhibits NKA by decreasing the pump affinity for internal Na(+) and this inhibition is relieved upon phosphorylation. Here we discuss the main characteristics of the Na(+) transport pathways in cardiac myocytes and their physiological and pathophysiological relevance.

Figure 1

Na⁺ and Ca²⁺ transport during cardiac cycle in ventricular myocytes. Inset shows the integrated Na flux through NCX, voltage-gated Na⁺ channels and NKA during an action potential (AP). The corresponding Ca²⁺ transient is also shown. NCX - Na⁺/Ca²⁺ exchanger; ATP - ATPase; PLB - phospholamban; PLM – phospholemman; SR - sarcoplasmic reticulum; NHE – Na/H exchanger. Modified from Bers (2001).