Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5

Michael Schaefer, Timothy D. Plant, Alexander G. Obukhov, Thomas Hofmann, Thomas Gudermann, Günter Schultz

Research output: Contribution to journalArticle

334 Scopus citations


Mammalian transient receptor potential channels (TRPCs) form a family of Ca2+-permeable cation channels currently consisting of seven members, TRPC1-TRPC7. These channels have been proposed to be molecular correlates for capacitative Ca2+ 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 Ca2+ 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 Mn2+ 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 (GTPγS). However, depletion of intracellular Ca2+ 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 GTPγS 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.

Original languageEnglish (US)
Pages (from-to)17517-17526
Number of pages10
JournalJournal of Biological Chemistry
Issue number23
StatePublished - Jun 9 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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