title: Molecular determinants of modulation of CaV2.1 channels by visinin-like protein 2.
abstract: CaV2.1 channels, which conduct P/Q-type Ca2+ currents, initiate synaptic transmission at most synapses in the central nervous system. Ca2+/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 CaV2.1 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 CaV2.1 channels. Here we examine the molecular determinants for differential regulation of CaV2.1 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 CaV2.1 channels. Our results identify the essential molecular determinants of differential regulation of CaV2.1 channels by VILIP-2 and define the molecular code that these proteins use to control short-term synaptic plasticity.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280.
authors.forename: Evanthia
authors.initials: E
authors.lastname: Nanou
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280.
authors.forename: Gilbert Q
authors.initials: GQ
authors.lastname: Martinez
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280.
authors.forename: Todd
authors.initials: T
authors.lastname: Scheuer
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280. Electronic address: wcatt@uw.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
mesh_terms: D020816:Amino Acid Motifs; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051596:Neurocalcin / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D020864:Calcium Channels, N-Type; D002147:Calmodulin; D051596:Neurocalcin
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