Trains of action potentials cause Ca2+-dependent facilitation and inactivat
ion of presynaptic P/Q-type Ca2+ channels that can alter synaptic efficacy.
A potential mechanism for these effects involves calmodulin, which associa
tes in a Ca2+-dependent manner with the pore-forming alpha(1A) subunit. Her
e, we report that Ca2+ and calmodulin dramatically enhance inactivation and
facilitation of P/Q-type Ca2+ channels containing the auxiliary beta(2a) s
ubunit compared with their relatively small effects on channels with beta(1
b). Tetanic stimulation causes an initial enhancement followed by a gradual
decline in P/Q-type Ca2+ currents over time. Recovery of Ca2+ currents fro
m facilitation and inactivation is relatively slow (30 sec to 1 min). These
effects are strongly inhibited by high intracellular BAPTA, replacement of
extracellular Ca2+ with Ba2+, and a calmodulin inhibitor peptide. The Ca2/calmodulin-dependent facilitation and inactivation of P/Q-type Ca2+ channe
ls observed here are consistent with the behavior of presynaptic Ca2+ chann
els in neurons, revealing how dual feedback regulation of P/Q-type channels
by Ca2+ and calmodulin could contribute to activity-dependent synaptic pla
sticity.