Modulation of Ca_V2.1 channels by Ca²⁺/calmodulin-dependent protein kinase II bound to the C-terminal domain

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 (Ca_V)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 Ca_V2.1 channels. The modulatory effects of CaMKII are reduced by a peptide that prevents binding to Ca_V2.1 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 Ca_V2.1 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 Ca_V2.1 channels initiate synaptic transmission and CaMKII has noncatalytic effects on presynaptic plasticity.

• calcium channels
• facilitation
• phosphorylation
• synaptic transmission