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 7.4 and 6.8. N-type Ca²⁺channels, which are intimately involved in exocytosis and other excitable cell processes, are sensitive to intracellular pH changes. However, the pH range over which N-type Ca²⁺ channels are sensitive, and the sensitivity of N-type Ca²⁺ channels to small 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. Intracellular pH was monitored in patch-clamp recordings with the fluorescent dye, BCECF, and manipulated in both the acidic and basic direction by extracellular application of NH₄ ⁺ in the presence and absence of intracellular NH₄ ⁺. Changes in intracellular pH between 6.6 and 7.5 produced a graded change in Ca²⁺ current magnitude with no apparent shift in activation potential. Intracellular acidification from pH 7.3 to 7.0 reversibly inhibited Ca²⁺ currents by 40%. Acidification from pH 7.3 to pH 6.6 reversibly inhibited Ca²⁺ currents 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 intracellular 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⁺ channel currents are extremely sensitive to small changes in pH_i in the range produced by both physiological and pathological events. Furthermore, these data suggest that modulation of N-type Ca²⁺ channels by pH_i may play an important role in physiological processes that produce small changes in pH_i and a protective role in pathological mechanisms that produce larger changes in pH_i.