The TRPM7 channel is inactivated by PIP(2) hydrolysis.
TRPM7 (ChaK1, TRP-PLIK, LTRPC7) is a ubiquitous, calcium-permeant ion channel that is unique in being both an ion channel and a serine/threonine kinase. The kinase domain of TRPM7 directly associates with the C2 domain of phospholipase C (PLC). Here, we show that in native cardiac cells and heterologous expression systems, G alpha q-linked receptors or tyrosine kinase receptors that activate PLC potently inhibit channel activity. Numerous experimental approaches demonstrated that phosphatidylinositol 4,5-bisphosphate (PIP(2)), the substrate of PLC, is a key regulator of TRPM7. We conclude that receptor-mediated activation of PLC results in the hydrolysis of localized PIP(2), leading to inactivation of the TRPM7 channel.
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Loren W
LW
Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Enders 1309, 320 Longwood Avenue, Boston, MA 02115, USA.
Yue
Lixia
L
Clapham
David E
DE
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D018679:Cholinergic Agonists / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D007473:Ion Channels / Q000378:metabolism*; D008565:Membrane Proteins; D008954:Models, Biological; D009206:Myocardium / Q000166:cytology; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D051381:Rats; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050053:TRPM Cation Channels; D020798:Two-Hybrid System Techniques; D010738:Type C Phospholipases / Q000378:metabolism*; D015003:Yeasts / Q000378:metabolism
D018679:Cholinergic Agonists; D004075:Diglycerides; D007473:Ion Channels; D008565:Membrane Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D011993:Recombinant Fusion Proteins; D050053:TRPM Cation Channels; D002217:Carbachol; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; C486584:Trpm7 protein, rat; D011493:Protein Kinase C; D010738:Type C Phospholipases