Molecular determinants of modulation of Ca V2.1 channels by visinin-like protein 2

Abstract

Ca V2.1 channels, which conduct P/Q-type Ca 2+ currents, initiate synaptic transmission at most synapses in the central nervous system. Ca 2+/calmodulin-dependent facilitation and inactivation of these channels contributes to short-term facilitation and depression of synaptic transmission, respectively. Other calcium sensor proteins displace calmodulin (CaM) from its binding site, differentially regulate Ca V2.1 channels, and contribute to the diversity of short-term synaptic plasticity. The neuronal calcium sensor protein visinin-like protein 2 (VILIP-2) inhibits inactivation and enhances facilitation of Ca V2.1 channels. Here we examine the molecular determinants for differential regulation of Ca V2.1 channels by VILIP-2 and CaM by construction and functional analysis of chimeras in which the functional domains of VILIP-2 are substituted in CaM. Our results show that the N-terminal domain, including its myristoylation site, the central α-helix, and the C-terminal lobe containing EF-hands 3 and 4 of VILIP-2 are sufficient to transfer its regulatory properties to CaM. This regulation by VILIP-2 requires binding to the IQ-like domain of Ca V2.1 channels. Our results identify the essential molecular determinants of differential regulation of Ca V2.1 channels by VILIP-2 and define the molecular code that these proteins use to control short-term synaptic plasticity. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.