PREFERENTIAL CLOSED-STATE INACTIVATION OF NEURONAL CALCIUM CHANNELS

We have investigated the inactivation mechanism of neuronal N-, P/Q-, and R-type calcium channels. Although channels inactivate slowly durin g square-pulse depolarization, as observed previously, we now find tha t they inactivate profoundly during a train of action potential (AP) w aveforms. The apparent paradox arises from a voltage-dependent mechani sm in which channels inactivate preferentially from intermediate close d states along the activation pathway. Inactivation can therefore exte nd beyond the brief duration of AP waveforms to continue between spike s, as the channel undergoes repetitive cycles of activation and deacti vation. The extent of inactivation during a train is strongly affected by the subunit composition of channels. Preferential closed-state ina ctivation of neuronal calcium channels could produce widely variable d epression of Ca2+ entry during a train of APs.