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The Journal of Neuroscience, July 27, 2005, 25(30):7062-7070; doi:10.1523/JNEUROSCI.0447-05.2005

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Cellular/Molecular
Modulation of Ca_V2.1 Channels by the Neuronal Calcium-Binding Protein Visinin-Like Protein-2

Nathan J. Lautermilch, Alexandra P. Few, Todd Scheuer, and William A. Catterall

Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280

Ca_V2.1 channels conduct P/Q-type Ca²⁺ currents that are modulated by calmodulin (CaM) and the structurally related Ca²⁺-binding protein 1 (CaBP1). Visinin-like protein-2 (VILIP-2) is a CaM-related Ca²⁺-binding protein expressed in the neocortex and hippocampus. Coexpression of Ca_V2.1 and VILIP-2 in tsA-201 cells resulted in Ca²⁺ channel modulation distinct from CaM and CaBP1. Ca_V2.1 channels with _2a subunits undergo Ca²⁺-dependent facilitation and inactivation attributable to association of endogenous Ca²⁺/CaM. VILIP-2 coexpression does not alter facilitation measured in paired-pulse experiments but slows the rate of inactivation to that seen without Ca²⁺/CaM binding and reduces inactivation of Ca²⁺ currents during trains of repetitive depolarizations. Ca_V2.1 channels with _1b subunits have rapid voltage-dependent inactivation, and VILIP-2 has no effect on the rate of inactivation or facilitation of the Ca²⁺ current. In contrast, when Ba²⁺ replaces Ca²⁺ as the charge carrier, VILIP-2 slows inactivation. The effects of VILIP-2 are prevented by deletion of the CaM-binding domain (CBD) in the C terminus of Ca_V2.1 channels. However, both the CBD and an upstream IQ-like domain must be deleted to prevent VILIP-2 binding. Our results indicate that VILIP-2 binds to the CBD and IQ-like domains of Ca_V2.1 channels like CaM but slows inactivation, which enhances facilitation of Ca_V2.1 channels during extended trains of stimuli. Comparison of VILIP-2 effects with those of CaBP1 indicates striking differences in modulation of both facilitation and inactivation. Differential regulation of Ca_V2.1 channels by CaM, VILIP-2, CaBP1, and other neurospecific Ca²⁺-binding proteins is a potentially important determinant of Ca²⁺ entry in neurotransmission.

Key words: facilitation; inactivation; neuromodulation; voltage clamp; synaptic plasticity; calcium current

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Received Feb 2, 2005; revised April 20, 2005; accepted May 14, 2005.

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