Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence.

The voltage-dependent calcium current of many neurons is depressed by transmitters such as noradrenaline, GABA, and kappa-opiate agonists. This modulation probably constitutes a major mechanism of presynaptic inhibition. Although recent work has implicated GTP-binding proteins in the mechanism of current inhibition, it is still unknown how the activation of those proteins alters the operation of the channels. In their initial description of the phenomenon, Dunlap and Fischbach proposed that noradrenaline acts by somehow reducing the number of functions calcium channels in the cell. By contrast with this hypothesis, I have found that inhibition of Ca2+ current is primarily due to a transmitter-induced change in the voltage-dependence with which channels are opened. Transmitters profoundly alter the voltage-dependence of channel activation, but there is little or no change in the number of functional channels activated by very large depolarizations. There is also little effect on the voltage-dependence of inactivation.