TY - JOUR T1 - Ca<sup>2+</sup> Regulation of Ca<sub>v</sub>3.3 T-type Ca<sup>2+</sup> Channel Is Mediated by Calmodulin JF - Molecular Pharmacology JO - Mol Pharmacol SP - 347 LP - 357 DO - 10.1124/mol.117.108530 VL - 92 IS - 3 AU - Narae Lee AU - Sua Jeong AU - Kang-Chang Kim AU - Jin-Ah Kim AU - Jin-Yong Park AU - Ho-Won Kang AU - Edward Perez-Reyes AU - Jung-Ha Lee Y1 - 2017/09/01 UR - http://molpharm.aspetjournals.org/content/92/3/347.abstract N2 - Calcium-dependent inactivation of high voltage-activated Ca2+ channels plays a crucial role in limiting rises in intracellular calcium (Ca2+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 Ca2+i can regulate low voltage-activated T-type Ca2+ channels. Using whole cell patch clamp, we examined the biophysical properties of Ca2+ current through the three T-type Ca2+ channel isoforms, Cav3.1, Cav3.2, or Cav3.3, comparing internal solutions containing 27 nM and l μM free Ca2+. Both activation and inactivation kinetics of Cav3.3 current in l μM Ca2+i solution were more rapid than those in 27 nM Ca2+i solution. In addition, both activation and steady-state inactivation curves of Cav3.3 were negatively shifted in the higher Ca2+i solution. In contrast, the biophysical properties of Cav3.1 and Cav3.2 isoforms were not significantly different between the two internal solutions. Overexpression of CaM1234 (a calmodulin mutant that doesn’t bind Ca2+) occluded the effects of l μM Ca2+i on Cav3.3, implying that CaM is involved in the Ca2+i regulation effects on Cav3.3. Yeast two-hybrid screening and co-immunoprecipitation experiments revealed a direct interaction of CaM with the carboxyl terminus of Cav3.3. Taken together, our results suggest that Cav3.3 T-type channel is potently regulated by Ca2+i via interaction of Ca2+/CaM with the carboxyl terminus of Cav3.3. ER -