H+-activated Na+ influx in the ventricular myocyte couples Ca2+-signalling to intracellular pH
Garciarena CD., Youm JB., Swietach P., Vaughan-Jones RD.
Acid extrusion on Na + -coupled pH-regulatory proteins (pH-transporters), Na + /H + exchange (NHE1) and Na + -HCO 3 - co-transport (NBC), drives Na + influx into the ventricular myocyte. This H + -activated Na + -influx is acutely up-regulated at pH i < 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". © 2013 Elsevier Ltd.