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Stimulation of recombinant Ca_v3.2, T-type, Ca²⁺ channel currents by CaMKII_C

Joshua T. Wolfe, Hongge Wang, Edward Perez-Reyes and Paula Q. Barrett

Molecular cloning of low-voltage activated (LVA) T-type calcium channels has enabled the study of their regulation in heterologous expression systems. Here we investigate the regulation of Ca_v3.2 ₁-subunits (1H) by calcium- and/or calmodulin-dependent protein kinase II (CaMKII). 293 cells stably expressing 1H were transiently transfected with CaMKII_C. Using the whole-cell recording configuration, we observed that elevation of pipette free Ca²⁺ (1 µM) in the presence of CaM (2 µM) increases T-type channel activity selectively at negative potentials, evoking an 11 mV hyperpolarizing shift in the half-maximal potential (V_1/2) for activation. The V_1/2 of channel inactivation is not altered by Ca²⁺/CaM. These effects reproduced modulation observed in adrenal zona glomerulosa cells. The potentiation by Ca²⁺/CaM was dependent on the co-expression of CaMKII_C and required Ca²⁺/CaM-dependent kinase activity. Peptide (AIP) and lipophilic (KN-62) protein kinase inhibitors prevented the Ca²⁺/CaM-induced changes in channel gating without altering basal Ca_v3.2 channel activity (27 nM free Ca²⁺) as did replacing pipette ATP with adenylyl imidodiphosphate (AMP-PNP), a non-hydrolysable analogue. CaMKII-dependent potentiation of channel opening resulted in significant increases in apparent steady-state open probability (P_o) and sustained channel current at negative voltages. Under identical conditions, CaMKII activation did not regulate the activity of Ca_v3.1 channels, the first cloned member (1G) of the T-type Ca²⁺ channel family. Our results provide the first evidence for the differential regulation of two members of the Ca_v3 family by protein kinase activation and the first report reconstituting CaMKII-dependent regulation of any cloned Ca²⁺ channel.

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