title: The molecular basis for T-type Ca2+ channel inhibition by G protein beta2gamma2 subunits.
abstract: Gbetagamma, a ubiquitous second messenger, relays external signals from G protein-coupled receptors to networks of intracellular effectors, including voltage-dependent calcium channels. Unlike high-voltage-activated Ca(2+) channels, the inhibition of low-voltage-activated Ca(2+) channels is subtype-dependent and mediated selectively by Gbeta(2)-containing dimers. Yet, the molecular basis for this exquisite selectivity remains unknown. Here, we used pure recombinant Gbetagamma subunits to establish that the Gbeta(2)gamma(2) dimer can selectively reconstitute the inhibition of alpha(1H) channels in isolated membrane patches. This inhibition is the result of a reduction in channel open probability that is not accompanied by a change in channel expression or an alteration in active-channel gating. By exchanging residues between the active Gbeta(2) subunit and the inactive Gbeta(1) subunit, we identified a cluster of amino acids that functionally distinguish Gbeta(2) from other Gbeta subunits. These amino acids on the beta-torus identify a region that is distinct from those regions that contact the Galpha subunit or other effectors.
authors.affiliation: Department of Pharmacology, University of Virginia, 1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
authors.forename: Seth D
authors.initials: SD
authors.lastname: DePuy
authors.forename: Junlan
authors.initials: J
authors.lastname: Yao
authors.forename: Changlong
authors.initials: C
authors.lastname: Hu
authors.forename: William
authors.initials: W
authors.lastname: McIntire
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bidaud
authors.forename: Philippe
authors.initials: P
authors.lastname: Lory
authors.forename: Fraydoon
authors.initials: F
authors.lastname: Rastinejad
authors.forename: Carlos
authors.initials: C
authors.lastname: Gonzalez
authors.forename: James C
authors.initials: JC
authors.lastname: Garrison
authors.forename: Paula Q
authors.initials: PQ
authors.lastname: Barrett
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002478:Cells, Cultured; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D021122:Protein Subunits / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D000596:Amino Acids; C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D021122:Protein Subunits; D011994:Recombinant Proteins