Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol

Nature. 1999 Jan 21;397(6716):259-63. doi: 10.1038/16711.


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). 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 membrane; this influx of Ca2+ may or may not be store-dependent. Drosophila transient receptor potential (TRP) proteins and some mammalian homologues (TRPC proteins) are thought to mediate capacitative Ca2+ entry. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium / metabolism*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Cell Membrane Permeability
  • Cloning, Molecular
  • Cricetinae
  • Diglycerides / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Estrenes / pharmacology
  • Histamine / metabolism
  • Humans
  • Ion Channel Gating
  • Ion Channels / metabolism*
  • Manganese / metabolism
  • Molecular Sequence Data
  • Patch-Clamp Techniques
  • Protein Kinase C / metabolism
  • Pyrrolidinones / pharmacology
  • Second Messenger Systems
  • TRPC Cation Channels
  • TRPC6 Cation Channel
  • Thapsigargin / pharmacology
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism


  • Calcium Channels
  • Diglycerides
  • Enzyme Inhibitors
  • Estrenes
  • Ion Channels
  • Pyrrolidinones
  • TRPC Cation Channels
  • TRPC3 cation channel
  • TRPC6 Cation Channel
  • TRPC6 protein, human
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • Manganese
  • Thapsigargin
  • Histamine
  • Protein Kinase C
  • Type C Phospholipases
  • Calcium

Associated data

  • GENBANK/AF080394