Influence of pH on Ca2+ current and its control of electrical and Ca2+ signaling in ventricular myocytes

Modulation of L-type Ca2+ current (I-Ca,I-L) by H+ ions in cardiac myocytes is controversial, with widely discrepant responses reported. The pH sensitivity of I-Ca,I-L was investigated (whole cell voltage clamp) while measuring intracellular Ca2+ (Ca-i(2+)) or pH(i) (epifluorescence microscopy) in rabbit and guinea pig ventricular myocytes. Selectively reducing extracellular or intracellular pH (pH(o) 6.5 and pH(i) 6.7) had opposite effects on I-Ca,I-L gating, shifting the steady-state activation and inactivation curves to the right and left, respectively, along the voltage axis. At low pH(o), this decreased I-Ca,I-L, whereas at low pH(i), it increased I-Ca,I-L at clamp potentials negative to 0 mV, although the current decreased at more positive potentials. When Ca-i(2+) was buffered with BAPTA, the stimulatory effect of low pH(i) was even more marked, with essentially no inhibition. We conclude that extracellular H+ ions inhibit whereas intracellular H+ ions can stimulate I-Ca,I-L. Low pH(i) and pH(o) effects on I-Ca,I-L were additive, tending to cancel when appropriately combined. They persisted after inhibition of calmodulin kinase II (with KN-93). Effects are consistent with H+ ion screening of fixed negative charge at the sarcolemma, with additional channel block by H-o(+) and Ca-i(2+). Action potential duration (APD) was also strongly H+ sensitive, being shortened by low pH(o), but lengthened by low pH(i), caused mainly by H(+-)induced changes in late Ca2+ entry through the L-type Ca2+ channel. Kinetic analyses of pH-sensitive channel gating, when combined with whole cell modeling, successfully predicted the APD changes, plus many of the accompanying changes in Ca2+ signaling. We conclude that the pH(i)-versus-pH(o) control of I-Ca,I-L will exert a major influence on electrical and Ca2+-dependent signaling during acid-base disturbances in the heart.