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Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol

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.

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Figure 1: Functional characterization of hTRPC6.
Figure 2: Regulation of hTRPC6.
Figure 3: Effect of DAG derivatives on hTRPC6 and rVR1 channels in inside-out patches.
Figure 4: Selective action of DAG derivatives on a subfamily of TRPC channels.

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Acknowledgements

We thank N. Albrecht for technical help with cell cultures, J.-C. Schwartz for providing the guinea pig H1 histamine receptor cDNA, and T. Plant for critically reading the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft.

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Correspondence to Günter Schultz.

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Hofmann, T., Obukhov, A., Schaefer, M. et al. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397, 259–263 (1999). https://doi.org/10.1038/16711

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