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Ca 2+ Regulation of Ca v 3.3 T-type Ca 2+ Channel Is Mediated by Calmodulin

Molecular Pharmacology, ISSN: 0026-895X, Vol: 92, Issue: 3, Page: 347-357
2017
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Calcium-dependent inactivation of high voltage-activated Ca 2+ channels plays a crucial role in limiting rises in intracellular calcium (Ca 2+ i ). A key mediator of these effects is calmodulin, which has been found to bind the C-terminus of the pore-forming α subunit. In contrast, little is known about how Ca 2+ i can regulate low voltage-activated T-type Ca 2+ channels. Using whole cell patch clamp, we examined the biophysical properties of Ca 2+ current through the three T-type Ca 2+ channel isoforms, Ca v 3.1, Ca v 3.2, or Ca v 3.3, comparing internal solutions containing 27 nM and l μM free Ca 2+. Both activation and inactivation kinetics of Ca v 3.3 current in l μM Ca 2+ i solution were more rapid than those in 27 nM Ca 2+ i solution. In addition, both activation and steady-state inactivation curves of Ca v 3.3 were negatively shifted in the higher Ca 2+ i solution. In contrast, the biophysical properties of Ca v 3.1 and Ca v 3.2 isoforms were not significantly different between the two internal solutions. Overexpression of CaM 1234 (a calmodulin mutant that doesn’t bind Ca 2+ ) occluded the effects of l μM Ca 2+ i on Ca v 3.3, implying that CaM is involved in the Ca 2+ i regulation effects on Ca v 3.3. Yeast two-hybrid screening and co-immunoprecipitation experiments revealed a direct interaction of CaM with the carboxyl terminus of Ca v 3.3. Taken together, our results suggest that Ca v 3.3 T-type channel is potently regulated by Ca 2+ i via interaction of Ca 2+ /CaM with the carboxyl terminus of Ca v 3.3.

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