5-HT₇Receptor Is Coupled to Gα Subunits of Heterotrimeric G12-Protein to Regulate Gene Transcription and Neuronal Morphology

Abstract

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-HT 4 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-HT 7 receptor. Expression of 5-HT 7 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-HT 7 receptor induced filopodia formation via a Cdc42-mediated pathway correlating with RhoA-dependent cell rounding. In mouse hippocampal neurons, activation of the endogenous 5-HT 7 receptors significantly increased neurite length, whereas stimulation of 5-HT 4 receptors led to a decrease in the length and number of neurites. These data demonstrate distinct roles for 5-HT 7 R/G12 and 5-HT 4 R/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.

Expression of 5-HT7 receptor mRNA in the hamster brain: Effect of aging and association with calbindin-D28K expression

“…As well as modulating photic phase shifts (Hamada et al, 2003), as described above, calbindin has been implicated in several other functions, including spatial memory, long-term potentiation in the hippocampus, synaptic plasticity, and either neuroprotection or enhanced vulnerability to neurodegeneration (Jouvenceau et al, 1999;Chard et al, 1995;Molinari et al, 1996;Nagerl et al, 2000). Some of these functions, such as memory, long-term potentiation, and synaptic plasticity are also modulated by 5-HT 7 receptors (Perez-Garcia et al, 2006;PerezGarcia and Meneses, 2005;Roberts et al, 2004;Kvachnina et al, 2005).…”

Biology of breast cancer during pregnancy using genomic profiling

“…CXCR4 and GPR30 are GPCRs that were shown to be of higher relevance in breast cancer; the former was found in preclinical models to increase the metastatic potential of breast cancer cells (Muller et al 2001), while the latter was linked to the process of endocrine resistance (Thomas et al 2005). The serotonin receptor pathway belongs to the GPCR family (Kvachnina et al 2005). Serotonin is known to play a role in mammary gland development (Matsuda et al 2004).…”

Stress- and antidepressant treatment-induced modifications of 5-HT7 receptor functions in the rat brain

“…Besides modulation of membrane excitability, activation of hippocampal 5-HT 7 receptors has been shown to stimulate neurite outgrowth [47]. Both Gas and Ga12 proteins can regulate cellular morphology by activating different signaling cascades.…”

“…Downstream Ga12 protein effectors, which mediate changes in the actin cytoskeleton, are members of the Rho family of small GTPases, including RhoA, Rac1 and Cdc42 [41]. The major functional effects of this pathway include actin reorganization and the formation of neurite-like protrusions and are mediated by the activation of Cdc42 [47]. It is proposed that the activation of the 5-HT 7 receptor by Gas and Ga12 proteins may stimulate glutamatergic synaptic transmission by a positive influence on a number of functional synapses.…”