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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 . 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 …