ACTION OF DIPHENYLAMINE CARBOXYLATE DERIVATIVES, A FAMILY OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS, ON [CA2+](I) AND CA2+-ACTIVATED CHANNELS IN NEURONS

Ca2+-activated channels, including Ca2+-activated non-selective (CAN) channels and Ca2+-activated Cl- channels play important roles in regulating the electrical activity of neurons. No blockers of neuronal CAN channels have been previously reported. We used 2-electrode voltage clamping to measure membrane currents and fura-2 fluorescence imaging to measure [Ca2+](i) in molluscan neurons. We show that the diphenylamine carboxylate derivative flufenamate (FFA), but not mefenamate or the parent compound, cause a transient increase in I-CAN and a slow outward current, and a maintained increase in [Ca2+](i). We interpret this as a FFA-dependent release of Ca2+ from intracellular stores and Ca2+ influx, [Ca2+](i)-dependent activation of the CAN and slow outward currents, and slow FFA-dependent channel block.