Proton-induced transformation in gating and selectivity of the calcium channel in neurons

Steady-state elevation of [H+]o inhibits both Ca2+ and Na+ currents in neurons. Step changes in [H+]o, however, induce a transient inward Na+ current (INa(H] in isolated neurons. In outside-out patches of dorsal root ganglion cells, INa(H) was fully activated within 2 ms at pH 6.7, and inactivated with a time constant of 300 ms. Deactivation t1/2 was 3 ms at pH 7.9. INa(H) was blocked by Ca2+ channel blockers. This observation, and the finding that the voltage-gated ICa disappeared rapidly during activation of INa(H) and reappeared with inactivation of INa(H), suggested that INa(H) occurs through a transformed Ca2+ channel. The proton-sensitive site was located at the external mouth of Ca2+ channel. The single channel conductance of INa(H) was 28 ps in symmetrical 120 mM NaCl solutions. Increase of [H+]o during the activation of ICa suppressed ICa within 2 ms. Our studies suggest that the Ca2+ channel exists in two conformational states; a voltage-gated Ca2+-transporting state, and a proton-gated Na+-transporting state. The dominance of the proton-gated state over the voltage-gated state suggests that proton modification of the Ca2+ channel may be extremely important in neurophysiological and neurosecretory function.