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      Novel and atypical pathways for serotonin signaling

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          Abstract

          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-HT 4, 5-HT 6, and 5-HT 7) signal through mechanisms that require neither G-proteins nor β-arrestins, the two classical and almost universal GPCR signal transducers. 5-HT 6 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-HT 6 receptor with Cdk5 and GPRIN1 are not concomitant but occur sequentially and play a key role in dendritic tree morphogenesis. Furthermore, 5-HT 6 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 mGlu 2 metabotropic glutamate receptors. This heteromerization results in a specific phosphorylation of mGlu 2 receptor on a serine residue (Ser 843) upon agonist stimulation of 5-HT 2A or mGlu 2 receptor. mGlu 2 receptor phosphorylation on Ser 843 is an essential step in engagement of G i/o signaling not only upon mGlu 2 receptor activation but also following 5-HT 2A receptor activation, and thus represents a key molecular event underlying functional crosstalk between both receptors.

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          Most cited references 81

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          Evolution and tinkering.

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            The dynamic process of β(2)-adrenergic receptor activation.

            G-protein-coupled receptors (GPCRs) can modulate diverse signaling pathways, often in a ligand-specific manner. The full range of functionally relevant GPCR conformations is poorly understood. Here, we use NMR spectroscopy to characterize the conformational dynamics of the transmembrane core of the β(2)-adrenergic receptor (β(2)AR), a prototypical GPCR. We labeled β(2)AR with (13)CH(3)ε-methionine and obtained HSQC spectra of unliganded receptor as well as receptor bound to an inverse agonist, an agonist, and a G-protein-mimetic nanobody. These studies provide evidence for conformational states not observed in crystal structures, as well as substantial conformational heterogeneity in agonist- and inverse-agonist-bound preparations. They also show that for β(2)AR, unlike rhodopsin, an agonist alone does not stabilize a fully active conformation, suggesting that the conformational link between the agonist-binding pocket and the G-protein-coupling surface is not rigid. The observed heterogeneity may be important for β(2)AR's ability to engage multiple signaling and regulatory proteins. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Molecular tinkering of G protein-coupled receptors: an evolutionary success.

               J P Pin,  J Bockaert (1999)
              Among membrane-bound receptors, the G protein-coupled receptors (GPCRs) are certainly the most diverse. They have been very successful during evolution, being capable of transducing messages as different as photons, organic odorants, nucleotides, nucleosides, peptides, lipids and proteins. Indirect studies, as well as two-dimensional crystallization of rhodopsin, have led to a useful model of a common 'central core', composed of seven transmembrane helical domains, and its structural modifications during activation. There are at least six families of GPCRs showing no sequence similarity. They use an amazing number of different domains both to bind their ligands and to activate G proteins. The fine-tuning of their coupling to G proteins is regulated by splicing, RNA editing and phosphorylation. Some GPCRs have been found to form either homo- or heterodimers with a structurally different GPCR, but also with membrane-bound proteins having one transmembrane domain such as nina-A, odr-4 or RAMP, the latter being involved in their targeting, function and pharmacology. Finally, some GPCRs are unfaithful to G proteins and interact directly, via their C-terminal domain, with proteins containing PDZ and Enabled/VASP homology (EVH)-like domains.
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                Author and article information

                Contributors
                Journal
                Fac Rev
                Fac Rev
                Faculty Reviews
                Faculty Reviews
                Faculty Opinions Ltd (London, UK )
                2732-432X
                01 June 2021
                2021
                : 10
                Affiliations
                [1 ]The Institute of Functional Genomics (IGF), University of Montpellier, CNRS, INSERM, Montpellier, France
                Author notes

                The authors declare that they have no competing interests.

                Article
                10.12703/r/10-52
                8204760
                34195691
                Copyright: © 2021 Bockaert J et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funding
                Funded by: University of Montpellier
                Funded by: iSITE Montpellier University of Excellence (MUSE)
                Funded by: Centre National de la Recherche Scientifique (CNRS
                Funded by: Institut National pour la Santé et la Recherche Médicale (INSERM)
                Funded by: Agence Nationale de la Recherche
                Award ID: ANR-17-CE16-0013-01
                Award ID: ANR-17-CE16-0010-01
                Award ID: ANR-19-CE18-0018-02
                The authors are supported by grants from University of Montpellier, iSITE Montpellier University of Excellence (MUSE), Centre National de la Recherche Scientifique (CNRS), Institut National pour la Santé et la Recherche Médicale (INSERM), and Agence Nationale de la Recherche (ANR, contracts n° ANR-17-CE16-0013-01, ANR-17-CE16-0010-01, and ANR-19-CE18-0018-02).
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Review Article

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