Action of diphenylamine carboxylate derivatives, a family of non-steroidal anti-inflammatory drugs, on [Ca2+]i and Ca(2+)-activated channels in neurons.

Ca(2+)-activated channels, including Ca(2+)-activated non-selective (CAN) channels and Ca(2+)-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 ICAN 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.