title: Calcium channel function regulated by the SH3-GK module in beta subunits.
abstract: beta subunits of voltage-gated calcium channels (VGCCs) regulate channel trafficking and function, thereby shaping the intensity and duration of intracellular changes in calcium. beta subunits share limited sequence homology with the Src homology 3-guanylate kinase (SH3-GK) module of membrane-associated guanylate kinases (MAGUKs). Here, we show biochemical similarities between beta subunits and MAGUKs, revealing important aspects of beta subunit structure and function. Similar to MAGUKs, an SH3-GK interaction within beta subunits can occur both intramolecularly and intermolecularly. Mutations that disrupt the SH3-GK interaction in beta subunits alter channel inactivation and can inhibit binding between the alpha(1) and beta subunits. Coexpression of beta subunits with complementary mutations in their SH3 and GK domains rescues these deficits through intermolecular beta subunit assembly. In MAGUKs, the SH3-GK module controls protein scaffolding. In beta subunits, this module regulates the inactivation of VGCCs and provides an additional mechanism for tuning calcium responsiveness.
authors.affiliation: Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: McGee
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nunziato
authors.forename: Janet M
authors.initials: JM
authors.lastname: Maltez
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Prehoda
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
authors.forename: David S
authors.initials: DS
authors.lastname: Bredt
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000502:physiology*; D004553:Electric Conductivity; D004594:Electrophysiology; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000502:physiology*; D051528:Guanylate Kinases; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials; D008958:Models, Molecular; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics; D009433:Neural Inhibition; D009703:Nucleoside-Phosphate Kinase / Q000502:physiology; D009865:Oocytes; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D017386:Sequence Homology, Amino Acid; D020798:Two-Hybrid System Techniques; D014981:Xenopus; D015003:Yeasts
chemical_list: C473930:ARHGEF26 protein, human; D015220:Calcium Channels; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; C033652:postsynaptic density proteins; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases