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

• Published in: The Journal of biological chemistry Vol. 284; no. 12; pp. 7465 - 7473
• Main Authors: Hu, Changlong, DePuy, Seth D., Yao, Junlan, McIntire, William E., Barrett, Paula Q.
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 20.03.2009
• Subjects: Membrane Transport, Structure, Function, and Biogenesis
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M808049200

Low voltage-activated (LVA), T-type, calcium channels mediate diverse biological functions and are inhibited by Gβγ dimers, yet the molecular events required for channel inhibition remain unknown. Here, we identify protein kinase A (PKA) as a molecular switch that allows Gβ 2 γx 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 Gβ 2 γ 2 dimers but does not disrupt dimer binding nor change its specificity. Gβγ dimers released upon receptor activation also require PKA activity for their inhibitory actions. Hence, dopamine inhibition of Ca v 3.2 whole cell current is precluded by Gβγ-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 Ca v 3.2 channel currents. We propose that a dual-receptor regulatory mechanism is used by dopamine to control Ca v 3.2 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.