Ca²⁺-dependent regulation of P/Q type Ca²⁺ channel activity: facilitation/depression and calmodulin

Abstract

Ca²⁺-dependent facilitation and inactivation of Cav2.1 channels modulate presynaptic P/Q-type Ca²⁺ currents. This dual feedback regulation by Ca²⁺ involves calmodulin (CaM) binding to the α1 subunit (α12.1). The molecular determinants for Ca²⁺-dependent modulation of Cav2.1 channels reside in CaM and in two CaM-binding sites in the C-terminal domain of α12.1, the CaM binding domain (CBD) and the IQ-like domain. In SCG neurons synapses transfected with brain-derived Cav2.1 channel and its mutants, Ca²⁺-dependent short-term synaptic plasticity, paired-pulse facilitation (PPF) and depression (PPD), augmentation and potentiation, was examined in the presence of Cav2.1 channels blocker, ω-conotoxin GVIA. PPF was completely prevented by alanine substitution of the first two residues of the IQ-like domain (IM-AA). In contrast, PPD was prevented by depletion of CBD (δCBD). Augmentation was reduced by IM-AA but not by δCBD. Potentiation was affected by neither IM-AA nor δCBD. These findings support a model in which Ca²⁺ binding to the C-terminal EF-hands of pre-associated CaM initiates facilitation of Cav2.1 channels via interaction with the IQ-like domain and initiates inactivation of Cav2.1 channels via interaction with CBD. This multifaceted mechanism allows positive and negative regulation of Cav2.1 channels in response to local Ca²⁺ increases. The Cav2.1 channel activity regulation, instead the residual Ca²⁺ at the active zone, is underlining the PPF, PPD and augmentation phenomena. [J Physiol Sci. 2007;57 Suppl:S14]