Endogenous and exogenous CA2+ buffers differentially modulate CA2+-dependent inactivation of CAV2.1 CA2+ channels

doi:10.1074/jbc.M511971200

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Papers In Press, published online ahead of print December 22, 2005
J. Biol. Chem, 10.1074/jbc.M511971200
Submitted on November 7, 2005
Revised on December 21, 2005
Accepted on December 22, 2005

Endogenous and exogenous CA²+ buffers differentially modulate CA²+-dependent inactivation of CAV2.1 CA²+ channels

Lisa Kreiner and Amy Lee

Pharmacology Dept., Emory University, Atlanta, GA 30322

Corresponding Author: alee{at}pharm.emory.edu

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 Cav2.1 (P/Q-type) Ca2+ channels is suppressed by strong cytoplasmic Ca2+ buffering, we investigated how factors that regulate cellular Ca2+ levels affect inactivation of Cav2.1 Ca2+ currents in transfected 293T cells. We found that inactivation of Cav2.1 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 Cav2.1. Cotransfection of Cav2.1 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 Cav2.1 depends on a subplasmalemmal Ca2+ microdomain that is affected by the amplitude of the Ca2+ current and differentially modulated by distinct Ca2+-buffers.

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