Differential modulation of Cav2.1 channels by calmodulin and Ca2+-binding protein 1

Abstract

Ca_v2.1 channels, which mediate P/Q-type Ca²⁺ currents, undergo Ca²⁺/calmodulin (CaM)-dependent inactivation and facilitation that can significantly alter synaptic efficacy. Here we report that the neuronal Ca²⁺-binding protein 1 (CaBP1) modulates Ca_v2.1 channels in a manner that is markedly different from modulation by CaM. CaBP1 enhances inactivation, causes a depolarizing shift in the voltage dependence of activation, and does not support Ca²⁺-dependent facilitation of Ca_v2.1 channels. These inhibitory effects of CaBP1 do not require Ca²⁺, but depend on the CaM-binding domain in the α₁ subunit of Ca_v2.1 channels (α₁2.1). CaBP1 binds to the CaM-binding domain, co-immunoprecipitates with α₁2.1 from transfected cells and brain extracts, and colocalizes with α₁2.1 in discrete microdomains of neurons in the hippocampus and cerebellum. Our results identify an interaction between Ca²⁺ channels and CaBP1 that may regulate Ca²⁺-dependent forms of synaptic plasticity by inhibiting Ca²⁺ influx into neurons.