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The Journal of Neuroscience, July 27, 2005, 25(30):7071-7080; doi:10.1523/JNEUROSCI.0452-05.2005

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Cellular/Molecular
Differential Regulation of Ca_V2.1 Channels by Calcium-Binding Protein 1 and Visinin-Like Protein-2 Requires N-Terminal Myristoylation

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

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

P/Q-type Ca²⁺ currents through presynaptic Ca_V2.1 channels initiate neurotransmitter release, and differential modulation of these channels by neuronal calcium-binding proteins (nCaBPs) may contribute to synaptic plasticity. The nCaBPs calcium-binding protein 1 (CaBP1) and visinin-like protein-2 (VILIP-2) differ from calmodulin (CaM) in that they have an N-terminal myristoyl moiety and one EF-hand that is inactive in binding Ca²⁺. To determine whether myristoylation contributes to their distinctive modulatory properties, we studied the regulation of Ca_V2.1 channels by the myristoyl-deficient mutants CaBP1/G2A and VILIP-2/G2A. CaBP1 positively shifts the voltage dependence of Ca_V2.1 activation, accelerates inactivation, and prevents paired-pulse facilitation in a Ca²⁺-independent manner. Block of myristoylation abolished these effects, leaving regulation that is similar to endogenous CaM. CaBP1/G2A binds to Ca_V2.1 with reduced stability, but in situ protein cross-linking and immunocytochemical studies revealed that it binds Ca_V2.1 in situ and is localized to the plasma membrane by coexpression with Ca_V2.1, indicating that it binds effectively in intact cells. In contrast to CaBP1, coexpression of VILIP-2 slows inactivation in a Ca²⁺-independent manner, but this effect also requires myristoylation. These results suggest a model in which nonmyristoylated CaBP1 and VILIP-2 bind to Ca_V2.1 channels and regulate them like CaM, whereas myristoylation allows differential, Ca²⁺-independent regulation by the inactive EF-hands of CaBP1 and VILIP-2, which differ in their positions in the protein structure. Differential, myristoylation-dependent regulation of presynaptic Ca²⁺ channels by nCaBPs may provide a flexible mechanism for diverse forms of short-term synaptic plasticity.

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

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Received Feb 2, 2005; revised June 13, 2005; accepted June 14, 2005.

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