Ca2+-independent Activation of Ca2+/Calmodulin-dependent Protein Kinase II Bound to the C-terminal Domain of CaV2.1 Calcium Channels |
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Authors: | Venkat G Magupalli Sumiko Mochida Jin Yan Xin Jiang Ruth E Westenbroek Angus C Nairn Todd Scheuer William A Catterall |
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Institution: | From the ‡Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280.;the §Department of Physiology, Tokyo Medical University, 160-8402 Tokyo, Japan, and ;the ¶Department of Psychiatry, Yale University, New Haven, Connecticut 06520 |
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Abstract: | Ca2+/calmodulin-dependent protein kinase II (CaMKII) forms a major component of the postsynaptic density where its functions in synaptic plasticity are well established, but its presynaptic actions are poorly defined. Here we show that CaMKII binds directly to the C-terminal domain of CaV2.1 channels. Binding is enhanced by autophosphorylation, and the kinase-channel signaling complex persists after dephosphorylation and removal of the Ca2+/CaM stimulus. Autophosphorylated CaMKII can bind the CaV2.1 channel and synapsin-1 simultaneously. CaMKII binding to CaV2.1 channels induces Ca2+-independent activity of the kinase, which phosphorylates the enzyme itself as well as the neuronal substrate synapsin-1. Facilitation and inactivation of CaV2.1 channels by binding of Ca2+/CaM mediates short term synaptic plasticity in transfected superior cervical ganglion neurons, and these regulatory effects are prevented by a competing peptide and the endogenous brain inhibitor CaMKIIN, which blocks binding of CaMKII to CaV2.1 channels. These results define the functional properties of a signaling complex of CaMKII and CaV2.1 channels in which both binding partners are persistently activated by their association, and they further suggest that this complex is important in presynaptic terminals in regulating protein phosphorylation and short term synaptic plasticity. |
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Keywords: | Calcium Calcium Channels Neurotransmitters Protein Kinases Protein Phosphorylation Synapses Synaptic Plasticity Nerve Terminal Signaling Complex |
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