Ca ²⁺/Calmodulin-Dependent Facilitation and Inactivation of P/Q-Type Ca ²⁺ Channels

Abstract

Trains of action potentials cause Ca ²⁺-dependent facilitation and inactivation of presynaptic P/Q-type Ca ²⁺ channels that can alter synaptic efficacy. A potential mechanism for these effects involves calmodulin, which associates in a Ca ²⁺-dependent manner with the pore-forming α _1A subunit. Here, we report that Ca ²⁺ and calmodulin dramatically enhance inactivation and facilitation of P/Q-type Ca ²⁺channels containing the auxiliary β _2a subunit compared with their relatively small effects on channels with β _1b. Tetanic stimulation causes an initial enhancement followed by a gradual decline in P/Q-type Ca ²⁺ currents over time. Recovery of Ca ²⁺ currents from facilitation and inactivation is relatively slow (30 sec to 1 min). These effects are strongly inhibited by high intracellular BAPTA, replacement of extracellular Ca ²⁺ with Ba ²⁺, and a calmodulin inhibitor peptide. The Ca ²⁺/calmodulin-dependent facilitation and inactivation of P/Q-type Ca ²⁺ channels observed here are consistent with the behavior of presynaptic Ca ²⁺ channels in neurons, revealing how dual feedback regulation of P/Q-type channels by Ca ²⁺ and calmodulin could contribute to activity-dependent synaptic plasticity.