Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol

Thomas Hofmann, Alexander G. Obukhov, Michael Schaefer, Christian Harteneck, Thomas Gudermann and Günter Schultz ()
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Thomas Hofmann: Institut fr Pharmakologie, Universittsklinikum Benjamin Franklin, Freie Universitt Berlin
Alexander G. Obukhov: Institut fr Pharmakologie, Universittsklinikum Benjamin Franklin, Freie Universitt Berlin
Michael Schaefer: Institut fr Pharmakologie, Universittsklinikum Benjamin Franklin, Freie Universitt Berlin
Christian Harteneck: Institut fr Pharmakologie, Universittsklinikum Benjamin Franklin, Freie Universitt Berlin
Thomas Gudermann: Institut fr Pharmakologie, Universittsklinikum Benjamin Franklin, Freie Universitt Berlin
Günter Schultz: Institut fr Pharmakologie, Universittsklinikum Benjamin Franklin, Freie Universitt Berlin

Nature, 1999, vol. 397, issue 6716, 259-263

Abstract: Abstract Eukaryotic cells respond to many hormones and neurotransmitters with increased activity of the enzyme phospholipase C and a subsequent rise in the concentration of intracellular free calcium ([Ca2+]i)1. The increase in [Ca2+]i occurs as a result of the release of Ca2+ from intracellular stores and an influx of Ca2+ through the plasma membrane2,3,4; this influx of Ca2+ may5 or may not6 be store-dependent. Drosophila transient receptor potential (TRP) proteins and some mammalian homologues (TRPC proteins) are thought to mediate capacitative Ca2+ entry7,8,9. Here we describe the molecular mechanism of store-depletion-independent activation of a subfamily of mammalian TRPC channels. We find that hTRPC6 is a non-selective cation channel that is activated by diacylglycerol in a membrane-delimited fashion, independently of protein kinases C activated by diacylglycerol. Although hTRPC3, the closest structural relative of hTRPC6, is activated in the same way, TRPCs 1, 4 and 5 and the vanilloid receptor subtype 1 are unresponsive to the lipid mediator. Thus, hTRPC3 and hTRPC6 represent the first members of a new functional family of second-messenger-operated cation channels, which are activated by diacylglycerol.

Date: 1999
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DOI: 10.1038/16711

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