Protein Kinase A Activity Controls the Regulation of T-type CaV3.2 Channels by Gβγ Dimers

Low voltage-activated (LVA), T-type, calcium channels mediate diverse biological functions and are inhibited by G beta gamma dimers, yet the molecular events required for channel inhibition remain unknown. Here, we identify protein kinase A (PKA) as a molecular switch that allows G beta(2)gamma x dimers to effect voltage-independent inhibition of Ca(v)3.2 channels. Inhibition requires phosphorylation of Ser(1107), a critical serine residue on the II-III loop of the channel pore protein. S1107A prevents inhibition of unitary currents by recombinant G beta(2)gamma x dimers but does not disrupt dimer binding nor change its specificity. G beta gamma dimers released upon receptor activation also require PKA activity for their inhibitory actions. Hence, dopamine inhibition of Cav3.2 whole cell current is precluded by G beta gamma-scavenger proteins or a peptide that blocks PKA catalytic activity. Fittingly, when used alone at receptor-selective concentrations, D-1 or D-2 agonists do not elicit channel inhibition yet together synergize to inhibit Cav3.2 channel currents. We propose that a dual-receptor regulatory mechanism is used by dopamine to control Cav3.2 channel activity. This mechanism, for example, would be important in aldosterone producing adrenal glomerulosa cells where channel dysregulation would lead to overproduction of aldosterone and consequent cardiac, renal, and brain target organ damage.