Ca2+/calmodulin-dependent facilitation and inactivation of P/Q-type Ca2+ channels.
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 alpha(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 beta(2a) subunit compared with their relatively small effects on channels with beta(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.
Lee
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A
Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.
Scheuer
T
T
Catterall
W A
WA
D000200:Action Potentials / Q000187:drug effects; D001464:Barium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004558:Electric Stimulation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D014162:Transfection
D001464:Barium; D002118:Calcium; D020864:Calcium Channels, N-Type; D002147:Calmodulin; D002614:Chelating Agents; D004533:Egtazic Acid; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006153:Guanosine Diphosphate; D013873:Thionucleotides; C023427:guanosine 5'-O-(2-thiodiphosphate); C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid