title: Protein kinase A activity controls the regulation of T-type CaV3.2 channels by Gbetagamma dimers.
abstract: Low voltage-activated (LVA), T-type, calcium channels mediate diverse biological functions and are inhibited by Gbetagamma dimers, yet the molecular events required for channel inhibition remain unknown. Here, we identify protein kinase A (PKA) as a molecular switch that allows Gbeta(2)gammax 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 Gbeta(2)gamma(2) dimers but does not disrupt dimer binding nor change its specificity. Gbetagamma 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 Gbetagamma-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.
authors.affiliation: Department of Pharmacology, Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Changlong
authors.initials: C
authors.lastname: Hu
authors.forename: Seth D
authors.initials: SD
authors.lastname: Depuy
authors.forename: Junlan
authors.initials: J
authors.lastname: Yao
authors.forename: William E
authors.initials: WE
authors.lastname: McIntire
authors.forename: Paula Q
authors.initials: PQ
authors.lastname: Barrett
mesh_terms: D000450:Aldosterone / Q000096:biosynthesis / Q000235:genetics; D019943:Amino Acid Substitution; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004298:Dopamine / Q000235:genetics / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D015384:Zona Glomerulosa / Q000378:metabolism*
chemical_list: C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type; D018491:Dopamine Agonists; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D000450:Aldosterone; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine