5-HT4 Receptor Activation of the ERK Pathway Depends on Src Activation but Not on G Protein or beta-Arrestin Signaling.

@article{citeulike:1214998, abstract = {Monitoring Editor: J. Silvio Gutkind The 5-HT4 receptors have recently emerged as key modulators of learning, memory and cognitive processes. In neurons, 5-HT4Rs activate cAMP production and PKA, however, nothing is known about their ability to activate another key signaling pathway involved in learning and memory: the 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 also observed that 5-HT4Rs in HEK293 cells, activated the ERK pathway in a Gs/cAMP/PKA-independent manner. We also demonstrated that other classical G proteins (Gq/Gi/Go) and associated downstream messengers were not implicated in the 5-HT4R-activated ERK pathway. The 5-HT4R-mediated ERK activation appeared to be dependent on Src tyrosine kinase and yet totally independent of beta-arrestin. Immunocytofluorescence revealed that p-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 = {Institut de G\'{e}nomique Fonctionnelle, Montpellier, F-34094, France; Centre National de la Recherche Scientifique Unit\'{e} Mixte de Recherche 5203, Montpellier, F-34094, France; Institut National de la Sant\'{e} et de la Recherche M\'{e}dicale, U661, Montpellier, F-34094, France; Universit\'{e} Montpellier I, Montpellier, F-34094, France; Universit\'{e} Montpellier II, Montpellier, F-34094, France; Institut National de la Recherche Agronomique, Unit\'{e} Mixte de Recherche 6175, Nouzilly, F-37380, France; Centre National de la Recherche Scientifique, Nouzilly, F-37380, France; Universit\'{e} Tours, Nouzilly, F-37380, France.}, author = {Barthet, Gael and Framery, B\'{e}r\'{e}nice and Gaven, Florence and Pellissier, Lucie and Reiter, Eric and Claeysen, Sylvie and Bockaert, Jo\"{e}l and Dumuis, Aline }, citeulike-article-id = {1214998}, doi = {10.1091/mbc.E06-12-1080}, issn = {1059-1524}, journal = {Mol Biol Cell}, keywords = {co-ip}, month = {March}, posted-at = {2007-04-07 15:12:43}, priority = {2}, title = {5-HT4 Receptor Activation of the ERK Pathway Depends on Src Activation but Not on G Protein or {beta}-Arrestin Signaling.}, url = {http://dx.doi.org/10.1091/mbc.E06-12-1080}, year = {2007} }

TY - JOUR ID - citeulike:1214998 L3 - citeulike-article-id:1214998 TI - 5-HT4 Receptor Activation of the ERK Pathway Depends on Src Activation but Not on G Protein or {beta}-Arrestin Signaling. JF - Mol Biol Cell AD - 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; Université Tours, Nouzilly, F-37380, France. SN - 1059-1524 N2 - Monitoring Editor: J. Silvio Gutkind The 5-HT4 receptors have recently emerged as key modulators of learning, memory and cognitive processes. In neurons, 5-HT4Rs activate cAMP production and PKA, however, nothing is known about their ability to activate another key signaling pathway involved in learning and memory: the 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 also observed that 5-HT4Rs in HEK293 cells, activated the ERK pathway in a Gs/cAMP/PKA-independent manner. We also demonstrated that other classical G proteins (Gq/Gi/Go) and associated downstream messengers were not implicated in the 5-HT4R-activated ERK pathway. The 5-HT4R-mediated ERK activation appeared to be dependent on Src tyrosine kinase and yet totally independent of beta-arrestin. Immunocytofluorescence revealed that p-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. KW - co-ip AU - Barthet, Gael AU - Framery, Bérénice AU - Gaven, Florence AU - Pellissier, Lucie AU - Reiter, Eric AU - Claeysen, Sylvie AU - Bockaert, Joël AU - Dumuis, Aline PY - 2007/03/21/ UR - http://dx.doi.org/10.1091/mbc.E06-12-1080 ER -