Intracellular Na+ regulation in cardiac myocytes

Abstract

Intracellular [Na+] ([Na+]i) is regulated in cardiac myocytes by a balance of Na+ influx and efflux mechanisms. In the normal cell there is a large steady state electrochemical gradient favoring Na+ influx. This potential energy is used by numerous transport mechanisms, including Na+ channels and transporters which couple Na+ influx to either co- or counter-transport of other ions and solutes. Six sarcolemmal Na+ influx pathways are discussed in relatively quantitative terms: Na+ channels, Na+/Ca2+ exchange, Na+/H+ exchange, Na+/Mg2+ exchange, Na+/HCO3- cotransport and Na+/K+/2Cl- cotransport. Under normal conditions Na+/Ca2+ exchange and Na+ channels are the dominant Na+ influx pathways, but other transporters may become increasingly important during altered conditions (e.g. acidosis or cell volume stress). Mitochondria also exhibit Na+/Ca2+ antiporter and Na+/H+ exchange activity that are important in mitochondrial function. These coupled fluxes of Na+ with Ca2+, H+ and HCO3- make the detailed understanding of [Na+]i regulation pivotal to the understanding of both cardiac excitation-contraction coupling and pH regulation. The Na+/K+-ATPase is the main route for Na+ extrusion from cells and [Na+]i is a primary regulator under physiological conditions. [Na+]i is higher in rat than rabbit ventricular myocytes and the reason appears to be higher Na+ influx in rat with a consequent rise in Na+/K+-ATPase activity (rather than lower Na+/K+-ATPase function in rat). This has direct functional consequences. There may also be subcellular [Na+]i gradients locally in ventricular myocytes and this may also have important functional implications. Thus, the balance of Na+ fluxes in heart cells may be complex, but myocyte Na+ regulation is functionally important and merits focused attention as in this issue.

Activity of the Na,K-ATPase α4 isoform is important for membrane potential, intracellular Ca2+, and pH to maintain motility in rat spermatozoa

“…The a4 isoform is not capable of directly transporting H C (Blanco et al 1999). Instead, and as has been shown for somatic cells (Bers et al 2003, Despa et al 2004, the Na,K-ATPase can functionally couple to the Na C /H C exchanger (NHE) to regulate pH in sperm. In this manner, the a4 isoform provides spermatozoa with an inwardly directed Na C gradient that provides the electrochemical energy to drive the secondary movement of protons out of the cells.…”

“…An important mechanism that controls proton concentration in somatic cells operates utilizing the transmembrane Na C gradient generated by the Na,K-ATPase. In this manner, the Na,K-ATPase indirectly controls pH in the cells (Bers et al 2003, Despa et al 2004. We explored whether the Na,K-ATPase plays a similar role in spermatozoa.…”

Clarifying the Arrhythmogenic Substrate for Brugada Syndrome Electroanatomic Mapping Study of the Right Ventricle

“…23,24) Furthermore, Royer, et al reported that aging Scn5a-knockout mice (Scn5a +/-) show progressive impairment of atrial and ventricular conduction associated with myocardial rearrangements and fibrosis, 25) and Papadatos, et al reported a reduction of approximately 50% in sodium conductance in Scn5a +/-mice as well as several defects including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. 26) Martin, et al also demonstrated that the electrocardiographic features in an Scn5a mouse establish it as a suitable model for Brugada syndrome and demonstrate abnormal conduction and repolarization phenomena.…”

Kinetic characterization of Na,K-ATPase inhibition by Eosin

“…The disequilibrium in ion transport makes the Na pump electrogenic. The Na + gradient created by the Na,K-ATPase is coupled to a multitude of secondary active transporters which mediate the uptake of amino acids, glucose, HCO 3 -, and neurotransmitters [1], as well as the extrusion of Ca ++ and H + [2]. Moreover, the maintenance of the Na + and K + gradients, in combination with selective ion channels, gives rise to resting membrane potential in most animal cells [for review see 3,4].…”