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Molecular Pharmacology

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Research ArticleORIGINAL ARTICLE

Negative Regulation of TRPC3 Channels by Protein Kinase C-Mediated Phosphorylation of Serine 712

Mohamed Trebak, Nadine Hempel, Barbara J. Wedel, Jeremy T. Smyth, Gary St. J. Bird and James W. Putney Jr.
Molecular Pharmacology February 2005, 67 (2) 558-563; DOI: https://doi.org/10.1124/mol.104.007252
Mohamed Trebak
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Nadine Hempel
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Barbara J. Wedel
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Jeremy T. Smyth
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Gary St. J. Bird
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James W. Putney Jr.
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Abstract

TRPC3 is a nonselective cation channel member of the “canonical” transient receptor potential (TRPC) family whose members are activated by phospholipase C-coupled receptors. TRPC3 can be activated by the diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) in a protein kinase C-independent manner. On the other hand, phorbol 12-myristate 13-acetate (PMA) inhibits OAG-mediated TRPC3 channel activation, suggesting that phosphorylation of TRPC3 by protein kinase C is a mechanism of receptor-mediated negative feedback. Here, we show PMA-induced phosphorylation of TRPC3 channels in vivo. We demonstrate by site-directed mutagenesis that a single site containing Ser712 and conserved among all members of the TRPC family is essential for protein kinase C-mediated negative regulation of TRPC3. In human embryonic kidney 293 cells expressing a TRPC3 mutant in which Ser712 was replaced by alanine (S712A), PMA failed to block channel activation, whereas wild-type TRPC3 activity was completely inhibited. Phosphorylation of the S712A TRPC3 mutant was not stimulated in response to PMA treatment. Furthermore, S712A TRPC3 mutant-mediated Ca2+ entry after methacholine activation was significantly greater than that of wild-type TRPC3. These findings demonstrate a dual role for phospholipase C-generated diacylglycerol, which serves as a signal for TRPC3 activation as well as a signal for negative feedback via protein kinase C-mediated phosphorylation.

  • Received September 14, 2004.
  • Accepted November 8, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (2)
Molecular Pharmacology
Vol. 67, Issue 2
1 Feb 2005
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Research ArticleORIGINAL ARTICLE

Negative Regulation of TRPC3 Channels by Protein Kinase C-Mediated Phosphorylation of Serine 712

Mohamed Trebak, Nadine Hempel, Barbara J. Wedel, Jeremy T. Smyth, Gary St. J. Bird and James W. Putney
Molecular Pharmacology February 1, 2005, 67 (2) 558-563; DOI: https://doi.org/10.1124/mol.104.007252

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Research ArticleORIGINAL ARTICLE

Negative Regulation of TRPC3 Channels by Protein Kinase C-Mediated Phosphorylation of Serine 712

Mohamed Trebak, Nadine Hempel, Barbara J. Wedel, Jeremy T. Smyth, Gary St. J. Bird and James W. Putney
Molecular Pharmacology February 1, 2005, 67 (2) 558-563; DOI: https://doi.org/10.1124/mol.104.007252
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