Key result
Inactivation of Ca(v)2.1 Ca2+ currents increased exponentially with current amplitude with 0.5 mM EGTA, but not with 10 mM BAPTA, indicating the importance of buffer kinetics.
The study demonstrates that Ca2+-dependent inactivation of Ca(v)2.1 channels is regulated by a subplasmalemmal Ca2+ microdomain and is highly sensitive to the kinetics of distinct Ca2+ buffers.
Buffer kinetics shape Ca(v)2.1 inactivation in animal models; leaves open relevance to human cardiac electrophysiology.
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(v)2.1 (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(v)2.1 Ca2+ currents in transfected 293T cells. We found that inactivation of Ca(v)2.1 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(v)2.1. Cotransfection of Ca(v)2.1 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(v)2.1 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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Kreiner et al. (2005) studied this question. Ca2+ buffers (EGTA, BAPTA, parvalbumin, calbindin) was evaluated on Ca2+-dependent inactivation of Ca(v)2.1 Ca2+ currents. Inactivation of Ca(v)2.1 Ca2+ currents increased exponentially with current amplitude with 0.5 mM EGTA, but not with 10 mM BAPTA, indicating the importance of buffer kinetics.
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