title: Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5.
abstract: Mammalian transient receptor potential channels (TRPCs) form a family of Ca(2+)-permeable cation channels currently consisting of seven members, TRPC1-TRPC7. These channels have been proposed to be molecular correlates for capacitative Ca(2+) entry channels. There are only a few studies on the regulation and properties of the subfamily consisting of TRPC4 and TRPC5, and there are contradictory reports concerning the possible role of intracellular Ca(2+) store depletion in channel activation. We therefore investigated the regulatory and biophysical properties of murine TRPC4 and TRPC5 (mTRPC4/5) heterologously expressed in human embryonic kidney cells. Activation of G(q/11)-coupled receptors or receptor tyrosine kinases induced Mn(2+) entry in fura-2-loaded mTRPC4/5-expressing cells. Accordingly, in whole-cell recordings, stimulation of G(q/11)-coupled receptors evoked large, nonselective cation currents, an effect mimicked by infusion of guanosine 5'-3-O-(thio)triphosphate (GTPgammaS). However, depletion of intracellular Ca(2+) stores failed to activate mTRPC4/5. In inside-out patches, single channels with conductances of 42 and 66 picosiemens at -60 mV for mTRPC4 and mTRPC5, respectively, were stimulated by GTPgammaS in a membrane-confined manner. Thus, mTRPC4 and mTRPC5 form nonselective cation channels that integrate signaling pathways from G-protein-coupled receptors and receptor tyrosine kinases independently of store depletion. Furthermore, the biophysical properties of mTRPC4/5 are inconsistent with those of I(CRAC), the most extensively characterized store-operated current.
authors.affiliation: Institut für Pharmakologie, Freie Universität Berlin, Thielallee 69-73, 14195 Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schaefer
authors.forename: T D
authors.initials: TD
authors.lastname: Plant
authors.forename: A G
authors.initials: AG
authors.lastname: Obukhov
authors.forename: T
authors.initials: T
authors.lastname: Hofmann
authors.forename: T
authors.initials: T
authors.lastname: Gudermann
authors.forename: G
authors.initials: G
authors.lastname: Schultz
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020013:Calcium Signaling; D027682:Cation Transport Proteins; D002460:Cell Line; D004963:Estrenes / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D007668:Kidney; D008345:Manganese / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D050052:TRPC Cation Channels; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection
chemical_list: D015220:Calcium Channels; D027682:Cation Transport Proteins; D004963:Estrenes; D007473:Ion Channels; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D050052:TRPC Cation Channels; C491780:TRPC5 protein, human; C112021:Trpc5 protein, mouse; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D008345:Manganese; D019284:Thapsigargin; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11