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Vol. 18, Issue 6, 1979-1991, June 2007

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5-Hydroxytryptamine₄ Receptor Activation of the Extracellular Signal-regulated Kinase Pathway Depends on Src Activation but Not on G Protein or -Arrestin Signaling

Gaël Barthet^*,,,,||, Bérénice Framery^*,,,,||, Florence Gaven^*,,,,||, Lucie Pellissier^*,,,,||, Eric Reiter^¶,#,@, Sylvie Claeysen^*,,,,||, Joël Bockaert^*,,,,||, and Aline Dumuis^*,,,,||

*Institut de Génomique Fonctionnelle, Montpellier F-34094, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, Montpellier F-34094, France; Institut National de la Santé et de la Recherche Médicale, U661, Montpellier F-34094, France; Université Montpellier I, Montpellier F-34094, France; ^||Université Montpellier II, Montpellier F-34094, France; ^¶Institut National de la Recherche Agronomique, Unité Mixte de Recherche 6175, Nouzilly F-37380, France; ^#Centre National de la Recherche Scientifique, Nouzilly F-37380, France; and ^@Université Tours, Nouzilly F-37380, France

Submitted December 6, 2006; Revised February 9, 2007; Accepted March 14, 2007
Monitoring Editor: J. Silvio Gutkind

The 5-hydroxytryptamine₄ (5-HT₄) receptors have recently emerged as key modulators of learning, memory, and cognitive processes. In neurons, 5-hydroxytryptamine₄ receptors (5-HT₄Rs) activate cAMP production and protein kinase A (PKA); however, nothing is known about their ability to activate another key signaling pathway involved in learning and memory: the extracellular signal-regulated kinase (ERK) pathway. Here, we show that 5-HT₄R stimulation, in primary neurons, produced a potent but transient activation of the ERK pathway. Surprisingly, this activation was mostly PKA independent. Similarly, using pharmacological, genetic, and molecular tools, we observed that 5-HT₄Rs in human embryonic kidney 293 cells, activated the ERK pathway in a G_s/cAMP/PKA-independent manner. We also demonstrated that other classical G proteins (G_q/G_i/G_o) and associated downstream messengers were not implicated in the 5-HT₄R–activated ERK pathway. The 5-HT₄R–mediated ERK activation seemed to be dependent on Src tyrosine kinase and yet totally independent of -arrestin. Immunocytofluorescence revealed that ERK activation by 5-HT₄R was restrained to the plasma membrane, whereas p-Src colocalized with the receptor and carried on even after endocytosis. This phenomenon may result from a tight interaction between 5-HT₄R and p-Src detected by coimmunoprecipitation. Finally, we confirmed that the main route by which 5-HT₄Rs activate ERKs in neurons was Src dependent. Thus, in addition to classical cAMP/PKA signaling pathways, 5-HT₄Rs may use ERK pathways to control memory process.

Address correspondence to: Joël Bockaert (joel.bockaert{at}igf.cnrs.fr).

Abbreviations used: ₂AR, ₂-adrenergic receptor; AT_1A, angiotensin II type 1A receptor; BSA, bovine serum albumin; C-t, carboxy terminal; ERK, extracellular signal-regulated kinase; GPCR, G protein-coupled receptor; HA, hemagglutinin; HEK, human embryonic kidney; 5-HT, 5-hydroxytryptamine (serotonin); 5-HT₄R, 5-hydroxytryptamine₄ receptor; IP, inositol phosphates; PI3K, phosphatidylinositol 3-kinase (PI3Ks); PKA, protein kinase A; V₂R, vasopressin 2 receptor; WT, wild type; YFP, yellow fluorescent protein.

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