Modulation of N-type Ca2+ channels by intracellular pH in chick sensory neurons

Both physiological and pathological neuronal events, many of which elevate intracellular [Ca2+], can produce changes in intracellular pH of between 0. 15 and 0.5 U, between pH 7.3 and 6.8. N-type Ca2+ channels, which are intim ately involved in exocytosis and other excitable cell processes, are sensit ive to intracellular pH changes. However, the pH range over which N-type Ca 2+ channels are sensitive, and the sensitivity of N-type Ca2+ channels to s mall changes in intracellular pH, are unknown. We studied the influence of intracellular pH changes on N-type calcium channel currents in dorsal root ganglion neurons, acutely isolated from 14-day-old chick embryos. Intracell ular pH was monitored in patch-clamp recordings with the fluorescent dye, B CECF, and manipulated in both the acidic and basic direction by extracellul ar application of NH4+ in the presence and absence of intracellular NH4+. C hanges in intracellular pH between 6.6 and 7.5 produced a graded change in Ca2+ current magnitude with no apparent shift in activation potential. Intr acellular acidification from pH 7.3 to 7.0 reversibly inhibited Ca2+ curren ts by 40%. Acidification from pH 7.3 to pH 6.6 reversibly inhibited Ca2+ cu rrents by 65%. Alkalinization from pH 7.3 to 7.5 potentiated Ca2+ currents by approximately 40%. Channels were sensitive to pH(i) changes with high in tracellular concentrations of the Ca2+ chelator, bis-(o-aminophenoxy)-N, N, N',N'-tetraacetic acid, which indicates that the effects of pH(i) did not involve a Ca2+-dependent mechanism. These data indicate that N-type Ca2+ ch annel currents are extremely sensitive to small changes in pH(i) in the ran ge produced by both physiological and pathological events. Furthermore, the se data suggest that modulation of N-type Ca2+ channels by pH(i) map play a n important role in physiological processes that produce small changes in p H(i) and a protective role in pathological mechanisms that produce larger c hanges in pH(i).