Modulation of Ca V 2.1 channels by Ca 2+ /calmodulin-dependent protein kinase II bound to the C-terminal domain

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Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of synaptic responses in the postsynaptic density, but understanding of its mechanisms of action in the presynaptic neuron is incomplete. Here we show that CaMKII constitutively associates with and modulates voltage-gated calcium (CaV)2.1 channels that conduct P/Q type Ca2+ currents and initiate transmitter release. Both exogenous and brain-specific inhibitors of CaMKII accelerate voltage-dependent inactivation, cause a negative shift in the voltage dependence of inactivation, and reduce Ca2+-dependent facilitation of CaV2.1 channels. The modulatory effects of CaMKII are reduced by a peptide that prevents binding to CaV2.1 channels but not by a peptide that blocks catalytic activity, suggesting that binding rather than phosphorylation is responsible for modulation. Our results reveal a signaling complex formed by CaV2.1 channels and CaMKII that regulates P/Q-type Ca2+ current in neurons. We propose an “effector checkpoint” model for the control of Ca2+ channel fitness for function that depends on association with CaMKII, SNARE proteins, and other effectors of Ca2+ signals. This regulatory mechanism would be important in presynaptic nerve terminals, where CaV2.1 channels initiate synaptic transmission and CaMKII has noncatalytic effects on presynaptic plasticity.