Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carbachol / pharmacology
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Cell Line
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Cholinergic Agonists / pharmacology
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Diglycerides / pharmacology
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Heart / drug effects
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Humans
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Hydrolysis
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Ion Channels / metabolism*
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Membrane Proteins*
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Models, Biological
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Myocardium / cytology
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Patch-Clamp Techniques
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Phosphatidylinositol 4,5-Diphosphate / metabolism*
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Protein Kinase C / metabolism
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases
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Protein Structure, Tertiary
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Rats
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Receptor, Muscarinic M1
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Receptors, Muscarinic / metabolism
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Recombinant Fusion Proteins / metabolism
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TRPM Cation Channels
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Two-Hybrid System Techniques
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Type C Phospholipases / metabolism*
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Yeasts / metabolism
Substances
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Cholinergic Agonists
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Diglycerides
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Ion Channels
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Membrane Proteins
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Phosphatidylinositol 4,5-Diphosphate
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Receptor, Muscarinic M1
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Receptors, Muscarinic
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Recombinant Fusion Proteins
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TRPM Cation Channels
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Carbachol
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Protein Kinases
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Protein Serine-Threonine Kinases
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TRPM7 protein, human
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Trpm7 protein, rat
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Protein Kinase C
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Type C Phospholipases