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Molecular Pharmacology

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Research ArticleORIGINAL ARTICLE

Palmitoylation of the 5-Hydroxytryptamine4a Receptor Regulates Receptor Phosphorylation, Desensitization, and β-Arrestin-Mediated Endocytosis

Evgeni Ponimaskin, Aline Dumuis, Florence Gaven, Gaël Barthet, Martin Heine, Konstantin Glebov, Diethelm W. Richter and Martin Oppermann
Molecular Pharmacology May 2005, 67 (5) 1434-1443; DOI: https://doi.org/10.1124/mol.104.008748
Evgeni Ponimaskin
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Aline Dumuis
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Florence Gaven
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Gaël Barthet
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Martin Heine
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Konstantin Glebov
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Diethelm W. Richter
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Martin Oppermann
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Abstract

The mouse 5-hydroxytryptamine4a (5-HT4a) receptor is an unusual member of the G protein-coupled receptor superfamily because it possesses two separate carboxyl-terminal palmitoylation sites, which may allow the receptor to adopt different conformations in an agonist-dependent manner (J Biol Chem 277:2534–2546, 2002). By targeted mutation of the proximal (Cys-328/329) or distal (Cys-386) palmitoylation sites, or a combination of both, we generated 5-HT4a receptor variants with distinct functional characteristics. In this study, we showed that upon 5-HT stimulation, the 5-HT4a receptor undergoes rapid (t½ ∼ 2 min) and dose-dependent (EC50 ∼ 180 nM) phosphorylation on serine residues by a staurosporine-insensitive receptor kinase. Overexpression of GRK2 significantly reduced the receptor-promoted cAMP formation. The Cys328/329-Ser mutant, which is constitutively active in the absence of ligand, exhibited enhanced receptor phosphorylation under both basal and agonist-stimulated conditions and was more effectively desensitized and internalized via a β-arrestin-2 mediated pathway compared with the wild-type 5-HT4a. In contrast, G protein activation, phosphorylation, desensitization, and internalization of the other palmitoylation-deficient receptor mutants were affected differently. These findings suggest that palmitoylation plays an important role in modulating 5-HT4a receptor functions and that G protein activation, phosphorylation, desensitization, and internalization depend on the different receptor conformations.

  • Received October 28, 2004.
  • Accepted February 2, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (5)
Molecular Pharmacology
Vol. 67, Issue 5
1 May 2005
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Research ArticleORIGINAL ARTICLE

Palmitoylation of the 5-Hydroxytryptamine4a Receptor Regulates Receptor Phosphorylation, Desensitization, and β-Arrestin-Mediated Endocytosis

Evgeni Ponimaskin, Aline Dumuis, Florence Gaven, Gaël Barthet, Martin Heine, Konstantin Glebov, Diethelm W. Richter and Martin Oppermann
Molecular Pharmacology May 1, 2005, 67 (5) 1434-1443; DOI: https://doi.org/10.1124/mol.104.008748

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Research ArticleORIGINAL ARTICLE

Palmitoylation of the 5-Hydroxytryptamine4a Receptor Regulates Receptor Phosphorylation, Desensitization, and β-Arrestin-Mediated Endocytosis

Evgeni Ponimaskin, Aline Dumuis, Florence Gaven, Gaël Barthet, Martin Heine, Konstantin Glebov, Diethelm W. Richter and Martin Oppermann
Molecular Pharmacology May 1, 2005, 67 (5) 1434-1443; DOI: https://doi.org/10.1124/mol.104.008748
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