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The Journal of Neuroscience, August 24, 2005, 25(34):7821-7830; doi:10.1523/JNEUROSCI.1790-05.2005

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Development/Plasticity/Repair
5-HT₇ Receptor Is Coupled to G Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

Elena Kvachnina,^1 * Guoquan Liu,^2 * Alexander Dityatev,³ Ute Renner,¹ Aline Dumuis,⁴ Diethelm W. Richter,¹ Galina Dityateva,³ Melitta Schachner,³ Tatyana A. Voyno-Yasenetskaya,² and Evgeni G. Ponimaskin¹

¹Abteilung Neurologie und Sinnesphysiologie, Physiologisches Institut, Universität Göttingen, Humboldtallee 23, 37073 Göttingen, Germany, ²Department of Pharmacology, University of Illinois, Chicago, Illinois 60612, ³Zentrum für Molekulare Neurobiologie, University of Hamburg, 20246 Hamburg, Germany, and ⁴ Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Universités Montpellier I and II, Montpellier F34094, France

The neurotransmitter serotonin (5-HT) plays an important role in the regulation of multiple events in the CNS. We demonstrated recently a coupling between the 5-HT₄ receptor and the heterotrimeric G13-protein resulting in RhoA-dependent neurite retraction and cell rounding (Ponimaskin et al., 2002). In the present study, we identified G12 as an additional G-protein that can be activated by another member of serotonin receptors, the 5-HT₇ receptor. Expression of 5-HT₇ receptor induced constitutive and agonist-dependent activation of a serum response element-mediated gene transcription through G12-mediated activation of small GTPases. In NIH3T3 cells, activation of the 5-HT₇ receptor induced filopodia formation via a Cdc42-mediated pathway correlating with RhoA-dependent cell rounding. In mouse hippocampal neurons, activation of the endogenous 5-HT₇ receptors significantly increased neurite length, whereas stimulation of 5-HT₄ receptors led to a decrease in the length and number of neurites. These data demonstrate distinct roles for 5-HT₇R/G12 and 5-HT₄R/G13 signaling pathways in neurite outgrowth and retraction, suggesting that serotonin plays a prominent role in regulating the neuronal cytoarchitecture in addition to its classical role as neurotransmitter.

Key words: 5-HT; serotonin; G-protein-coupled receptor; heterotrimeric G-protein; small GTPases; gene transcription; neuronal morphology

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Received Jan 6, 2005; revised July 7, 2005; accepted July 8, 2005.

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