Ca2+/calmodulin binds to and modulates P/Q-type calcium channels.
Neurotransmitter release at many central synapses is initiated by an influx of calcium ions through P/Q-type calcium channels, which are densely localized in nerve terminals. Because neurotransmitter release is proportional to the fourth power of calcium concentration, regulation of its entry can profoundly influence neurotransmission. N- and P/Q-type calcium channels are inhibited by G proteins, and recent evidence indicates feedback regulation of P/Q-type channels by calcium. Although calcium-dependent inactivation of L-type channels is well documented, little is known about how calcium modulates P/Q-type channels. Here we report a calcium-dependent interaction between calmodulin and a novel site in the carboxy-terminal domain of the alpha1A subunit of P/Q-type channels. In the presence of low concentrations of intracellular calcium chelators, calcium influx through P/Q-type channels enhances channel inactivation, increases recovery from inactivation and produces a long-lasting facilitation of the calcium current. These effects are prevented by overexpression of a calmodulin-binding inhibitor peptide and by deletion of the calmodulin-binding domain. Our results reveal an unexpected association of Ca2+/calmodulin with P/Q-type calcium channels that may contribute to calcium-dependent synaptic plasticity.
Lee
A
A
Department of Pharmacology, University of Washington, Seattle 98195-7280, USA.
Wong
S T
ST
Gallagher
D
D
Li
B
B
Storm
D R
DR
Scheuer
T
T
Catterall
W A
WA
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020864:Calcium Channels, N-Type; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D002614:Chelating Agents; D003001:Cloning, Molecular; D004533:Egtazic Acid; D008969:Molecular Sequence Data; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015003:Yeasts
D002118:Calcium; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D002147:Calmodulin; D002614:Chelating Agents; D004533:Egtazic Acid; D011993:Recombinant Fusion Proteins