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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




Journal article


J Mol Cell Cardiol

Publication Date





51 - 59


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 Antiporter