Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol

• Published in: Nature (London) Vol. 397; no. 6716; pp. 259 - 263
• Main Authors: Schultz, Günter, Hofmann, Thomas, Obukhov, Alexander G, Schaefer, Michael, Harteneck, Christian, Gudermann, Thomas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 21.01.1999; Nature Publishing Group
• Subjects: Animals; Biochemistry; Biological and medical sciences; Calcium; Calcium - metabolism; Calcium Channels - genetics; Calcium Channels - metabolism; Cell Membrane Permeability; Cell membranes. Ionic channels. Membrane pores; Cell structures and functions; Cells; CHO Cells; Cloning, Molecular; Cricetinae; Diglycerides - metabolism; Enzyme Inhibitors - pharmacology; Estrenes - pharmacology; Fundamental and applied biological sciences. Psychology; Histamine - metabolism; Hormones; Humans; Ion Channel Gating; Ion Channels - metabolism; Mammals; Manganese - metabolism; Molecular and cellular biology; Molecular Sequence Data; Patch-Clamp Techniques; Protein Kinase C - metabolism; Pyrrolidinones - pharmacology; Second Messenger Systems; Thapsigargin - pharmacology; TRPC Cation Channels; TRPC6 Cation Channel; Type C Phospholipases - antagonists & inhibitors; Type C Phospholipases - metabolism; Human; Electrophysiology; Regulation(control); Ionic channel; Calcium Ions; Diglyceride
• ISSN: 0028-0836; 1476-4687
• 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.