Novel and atypical pathways for serotonin signaling

Serotonin (5-HT) appeared billions of years before 5-HT receptors and synapses. It is thus not surprising that 5-HT can control biological processes independently of its receptors. One example is serotonylation, which consists of covalent binding of 5-HT to the primary amine of glutamine. Over the past 20 years, serotonylation has been involved in the regulation of many signaling mechanisms. One of the most striking examples is the recent evidence that serotonylation of histone H3 constitutes an epigenetic mark. However, the pathophysiological role of histone H3 serotonylation remains to be discovered. All but one of the 5-HT receptors are G-protein-coupled receptors (GPCRs). The signaling pathways they control are finely tuned, and new, unexpected regulatory mechanisms are being uncovered continuously. Some 5-HT receptors (5-HT_2C, 5-HT₄, 5-HT₆, and 5-HT₇) signal through mechanisms that require neither G-proteins nor β-arrestins, the two classical and almost universal GPCR signal transducers. 5-HT₆ receptors are constitutively activated via their association with intracellular GPCR-interacting proteins (GIPs), including neurofibromin 1, cyclin-dependent kinase 5 (Cdk5), and G-protein-regulated inducer of neurite outgrowth 1 (GPRIN1). Interactions of 5-HT₆ receptor with Cdk5 and GPRIN1 are not concomitant but occur sequentially and play a key role in dendritic tree morphogenesis. Furthermore, 5-HT₆ receptor-mediated G-protein signaling in neurons is different in the cell body and primary cilium, where it is modulated by smoothened receptor activation. Finally, 5-HT_2A receptors form heteromers with mGlu₂ metabotropic glutamate receptors. This heteromerization results in a specific phosphorylation of mGlu₂ receptor on a serine residue (Ser⁸⁴³) upon agonist stimulation of 5-HT_2A or mGlu₂ receptor. mGlu₂ receptor phosphorylation on Ser⁸⁴³ is an essential step in engagement of G_i/o signaling not only upon mGlu₂ receptor activation but also following 5-HT_2A receptor activation, and thus represents a key molecular event underlying functional crosstalk between both receptors.