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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{alpha} 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


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




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