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J. Biol. Chem., Vol. 281, Issue 8, 4691-4698, February 24, 2006

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Endogenous and Exogenous Ca²⁺ Buffers Differentially Modulate Ca²⁺-dependent Inactivation of Ca_V2.1 Ca²⁺ Channels^*

From the Department of Pharmacology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322

Voltage-gated Ca²⁺ channels undergo a negative feedback regulation by Ca²⁺ ions, Ca²⁺-dependent inactivation, which is important for restricting Ca²⁺ signals in nerve and muscle. Although the molecular details underlying Ca²⁺-dependent inactivation have been characterized, little is known about how this process might be modulated in excitable cells. Based on previous findings that Ca²⁺-dependent inactivation of Ca_v2.1 (P/Q-type) Ca²⁺ channels is suppressed by strong cytoplasmic Ca²⁺ buffering, we investigated how factors that regulate cellular Ca²⁺ levels affect inactivation of Ca_v2.1 Ca²⁺ currents in transfected 293T cells. We found that inactivation of Ca_v2.1 Ca²⁺ currents increased exponentially with current amplitude with low intracellular concentrations of the slow buffer EGTA (0.5 mM), but not with high concentrations of the fast Ca²⁺ buffer BAPTA (10 mM). However, when the concentration of BAPTA was reduced to 0.5 mM, inactivation of Ca²⁺ currents was significantly greater than with an equivalent concentration of EGTA, indicating the importance of buffer kinetics in modulating Ca²⁺-dependent inactivation of Ca_v2.1. Cotransfection of Ca_v2.1 with the EF-hand Ca²⁺-binding proteins, parvalbumin and calbindin, significantly altered the relationship between Ca²⁺ current amplitude and inactivation in ways that were unexpected from behavior as passive Ca²⁺ buffers. We conclude that Ca²⁺-dependent inactivation of Ca_v2.1 depends on a subplasmalemmal Ca²⁺ microdomain that is affected by the amplitude of the Ca²⁺ current and differentially modulated by distinct Ca²⁺ buffers.

Received for publication, November 7, 2005 , and in revised form, December 21, 2005.

^* This work was supported by Grant NS044922 from the National Institutes of Health (to A. L.), the Whitehall Foundation, and a Predoctoral NRSA Grant F31NS049757 (to L. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, Emory University School of Medicine, 5123 Rollins Research Bldg., 1510 Clifton Rd., Atlanta, GA 30322. Tel.: 404-727-5991; Fax: 404-727-0365; E-mail: alee{at}pharm.emory.edu.

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