5-Hydroxytryptamine 4(a) receptor is coupled to the Galpha subunit of heterotrimeric G13 protein.

Serotonin (5-hydroxytryptamine (5-HT)) is an important neurotransmitter that regulates multiple events in the central nervous system. Many of the 5-HT functions are mediated via G protein-coupled receptors that are coupled to multiple heterotrimeric G proteins, including G(s), G(i), and G(q) subfamilies (Martin, G. R., Eglen, R. M., Hamblin, M. W., Hoyer, D., and Yocca, F. (1998) Trends Pharmacol. Sci. 19, 2-4). Here we show for the first time that the 5-hydroxytryptamine 4(a) receptor (5-HT(4(a))) is coupled not only to heterotrimeric G(s) but also to G(13) protein, as assessed both by biochemical and functional assays. Using reconstitution of 5-HT(4(a)) receptor with different G proteins in Spodoptera frugiperda (Sf.9) cells, we have proved that agonist stimulation of receptor-induced guanosine 5'-(3-O-thio)triphosphate binding to Galpha(13) protein. We then determined that expression of 5-HT(4(a)) receptor in mammalian cells induced constitutive- as well as agonist-promoted activation of a transcription factor, serum response element, through the activation of Galpha(13) and RhoA. Finally, we have determined that expression of 5-HT(4(a)) receptor in neuroblastoma x glioma NIE-115 cells cause RhoA-dependent neurite retraction and cell rounding under basal conditions and after agonist stimulation. These data suggest that by activating 5-HT(4(a)) receptor-G(13) pathway, serotonin plays a prominent role in regulating neuronal architecture in addition to its classical role in neurotransmission.