Signaling mechanism for receptor-activated canonical transient receptor potential 3 (TRPC3) channels.
Canonical transient receptor potential 3 (TRPC3) is a receptor-activated, calcium permeant, non-selective cation channel. TRPC3 has been shown to interact physically with the N-terminal domain of the inositol 1,4,5-trisphosphate receptor, consistent with a "conformational coupling" mechanism for its activation. Here we show that low concentrations of agonists that fail to produce levels of inositol 1,4,5-trisphosphate sufficient to induce Ca(2+) release from intracellular stores substantially activate TRPC3. By several experimental approaches, we demonstrate that neither inositol 1,4,5-trisphosphate nor G proteins are required for TRPC3 activation. However, diacylglycerols were sufficient to activate TRPC3 in a protein kinase C-independent manner. Surface receptor agonists and exogenously applied diacylglycerols were not additive in activating TRPC3. In addition, inhibition of metabolism of diacylglycerol slowed the reversal of receptor-dependent TRPC3 activation. We conclude that receptor-mediated activation of phospholipase C in intact cells activates TRPC3 via diacylglycerol production, independently of G proteins, protein kinase C, or inositol 1,4,5-trisphosphate.
Trebak
Mohamed
M
Laboratory of Signal Transduction, NIEHS/National Institutes of Health, Research Triangle Park, NC 27709, USA.
St  J  Bird
Gary
G
McKay
Richard R
RR
Birnbaumer
Lutz
L
Putney
James W
JW
D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D016210:Methacholine Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D050052:TRPC Cation Channels; D010738:Type C Phospholipases / Q000378:metabolism
D015220:Calcium Channels; D004075:Diglycerides; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D050052:TRPC Cation Channels; D016210:Methacholine Chloride; D004815:Epidermal Growth Factor; D015544:Inositol 1,4,5-Trisphosphate; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D002118:Calcium