Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Acid extrusion on Na(+)-coupled pH-regulatory proteins (pH-transporters), Na(+)/H(+) exchange (NHE1) and Na(+)-HCO3(-) co-transport (NBC), drives Na(+) influx into the ventricular myocyte. This H(+)-activated Na(+)-influx is acutely up-regulated at pHi<7.2, greatly exceeding Na(+)-efflux on the Na(+)/K(+) ATPase. It is spatially heterogeneous, due to the co-localisation of NHE1 protein (the dominant pH-transporter) with gap-junctions at intercalated discs. Overall Na(+)-influx via NBC is considerably lower, but much is co-localised with L-type Ca(2+)-channels in transverse-tubules. Through a functional coupling with Na(+)/Ca(2+) exchange (NCX), H(+)-activated Na(+)-influx increases sarcoplasmic-reticular Ca(2+)-loading and release during intracellular acidosis. This raises Ca(2+)-transient amplitude, rescuing it from direct H(+)-inhibition. Functional coupling is biochemically regulated and linked to membrane receptors, through effects on NHE1 and NBC. It requires adequate cytoplasmic Na(+)-mobility, as NHE1 and NCX are spatially separated (up to 60μm). The relevant functional NCX activity must be close to dyads, as it exerts no effect on bulk diastolic Ca(2+). H(+)-activated Na(+)-influx is up-regulated during ischaemia-reperfusion and some forms of maladaptive hypertrophy and heart failure. It is thus an attractive system for therapeutic manipulation. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

Original publication

DOI

10.1016/j.yjmcc.2013.04.008

Type

Journal article

Journal

J Mol Cell Cardiol

Publication Date

08/2013

Volume

61

Pages

51 - 59

Keywords

CA, CBE, CHE, Ca(2+) transient, CaT, Cl(−)/HCO(3)(−) exchange, Cl(−)/OH(−) exchange, DAD, LTCC, MAPK, MCT, NBC, NCX, NHE, Na(+)-HCO(3)(−) co-transport, Na(+)-influx, Na(+)/Ca(2+) exchange, Na(+)/H(+) exchange, PKC, PMCA, RyR, SERCA, SR, acidosis, carbonic anhydrase, delayed after-depolarisation, intracellular pH, mitogen activated protein kinase, monocarboxylic acid transporter, pH regulatory proteins, pH transporters, pH(i), pH(i)-regulation, plasmalemmal Ca(2+) ATPase, protein kinase C, ryanodine receptor, sarcolemmal L-type Ca(2+) channel, sarcoplasmic reticular Ca(2+) ATPase, sarcoplasmic reticulum, t-tubules, transverse tubules, Acid-Base Imbalance, Animals, Cardiomegaly, Cation Transport Proteins, Excitation Contraction Coupling, Heart Failure, Heart Ventricles, Humans, Myocardial Reperfusion Injury, Myocytes, Cardiac, Protons, Sodium-Hydrogen Exchanger 1, Sodium-Hydrogen Exchangers