5-hydroxytryptamine 4 Receptor Activation of the Extracellular Signal-regulated Kinase Pathway Depends on Src Activation but Not on G Protein or Beta-arrestin Signaling.
From: Institut de Génomique Fonctionnelle, Montpellier F-34094, France.
Molecular biology of the cell
- Publish Date: Jun 2007
- ISSN: 1059-1524
- Volume: 18
- Issue: 6
- Pages: 1979-91
- Medium: Print
- Language: English
- Citation (JAMA): Barthet Gaël, Framery Bérénice, Gaven Florence, et al. 5-hydroxytryptamine 4 Receptor Activation of the Extracellular Signal-regulated Kinase Pathway Depends on Src Activation but Not on G Protein or Beta-arrestin Signaling.. Mol. Biol. Cell Jun 2007;18:1979-91
Abstract
The 5-hydroxytryptamine(4) (5-HT(4)) receptors have recently emerged as key modulators of learning, memory, and cognitive processes. In neurons, 5-hydroxytryptamine(4) receptors (5-HT(4)Rs) 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-HT(4)R 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-HT(4)Rs 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-HT(4)R-activated ERK pathway. The 5-HT(4)R-mediated ERK activation seemed to be dependent on Src tyrosine kinase and yet totally independent of beta-arrestin. Immunocytofluorescence revealed that ERK activation by 5-HT(4)R 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-HT(4)R and p-Src detected by coimmunoprecipitation. Finally, we confirmed that the main route by which 5-HT(4)Rs activate ERKs in neurons was Src dependent. Thus, in addition to classical cAMP/PKA signaling pathways, 5-HT(4)Rs may use ERK pathways to control memory process.
Mesh Headings (Keywords): Amino Acid Sequence, Animals, Arrestins, Cells, Cultured, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, GTP-Binding Proteins, Humans, MAP Kinase Signaling System, Mice, Molecular Sequence Data, Neurons, RNA, Small Interfering, Receptors, Serotonin, 5-HT4, src-Family Kinases
Check for Full Text / PubMed Unique Identifier (PMID): 17377064
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