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

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, Ca²⁺ enters the myocytes via L-type Ca ²⁺ channels. This triggers Ca²⁺ release from the sarcoplasmic reticulum (SR) and thus activates contraction. Relaxation occurs when cytosolic Ca²⁺ declines, mainly due to re-uptake into the SR via SR Ca²⁺-ATPase and extrusion from the cell via the Na ⁺/Ca²⁺ exchanger (NCX). NCX extrudes one Ca²⁺ 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.