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Review
. 2021 Jun 1:10:52.
doi: 10.12703/r/10-52. eCollection 2021.

Novel and atypical pathways for serotonin signaling

Joël Bockaert  1 , Carine Bécamel  1 , Séverine Chaumont-Dubel  1 , Sylvie Claeysen  1 , Franck Vandermoere  1 , Philippe Marin  1
Affiliations
Review

Novel and atypical pathways for serotonin signaling

Joël Bockaert et al. Fac Rev. .

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-HT2C, 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-HT2A 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-HT2A or mGlu2 receptor. mGlu2 receptor phosphorylation on Ser843 is an essential step in engagement of Gi/o signaling not only upon mGlu2 receptor activation but also following 5-HT2A receptor activation, and thus represents a key molecular event underlying functional crosstalk between both receptors.

Keywords: GPCR interacting protein; Serotonin; heteromerization; receptor; serotonylation.

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Conflict of interest statement

The authors declare that they have no competing interests.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. 5-HT signaling via G-protein-coupled receptors (GPCRs) and serotonylation.
5-HT controls cell signaling via its cognate receptors (mostly GPCRs) and intracellularly via transamidation (serotonylation) of specific proteins. Note that extracellular proteins can also be serotonylated (not illustrated). Owing to the hydrophilic nature of 5-HT, serotonylation is believed to occur only in cells expressing the serotonin transporter (SERT). In the example illustrated in the figure, 5-HT2A/C receptor stimulation by 5-HT induces activation of phospholipase C (PLC), and thereby an increase in intracellular Ca2+ concentration, a process leading to a full activation of the transglutaminase TG2.
Figure 2.
Figure 2.. Specific proteins serotonylated by transglutaminases in different cell types.
Examples of intracellular and extracellular serotonylated proteins in platelets, vascular smooth muscle cells, valve interstitial cells, pancreatic β-cells, neurons, and glial cells are illustrated. The right panel shows serotonylated histone H3 at position 5 (Q5ser) by transglutaminase 2 (TG2) predominantly in combination with trimethylation of adjacent lysine (K)4, resulting in the double epigenetic mark H3K4me3Q5ser. SERT, serotonin transporter; TFIID, transcription factor II D; VMAT2, vesicular monoamine transporter 2.
Figure 3.
Figure 3.. Non-G-protein signaling at 5-HT receptors.
Top: the 5-HT4 receptor engages Erk1,2 signaling in neurons through a Gs- and β-arrestin-independent mechanism that requires activation of the non-receptor tyrosine kinase Src. In the intestinal epithelial Caco-2 cell line, 5-HT4 receptor-mediated Src activation leads to phospholipase C (PLC)/Ca2+-calmodulin-dependent inhibition of the Na+/H+ exchanger. *Constitutively active receptors. Bottom left: the 5-HT2C receptor engages Erk1,2 signaling in neurons through a G-protein-independent, β-arrestin-dependent mechanism that requires physical association of calmodulin with the receptor’s C-terminal domain. Bottom, middle: the 5-HT6 receptor activates the cyclin-dependent kinase 5 (Cdk5)–Cdc42 signaling pathway in an agonist-independent manner through a reciprocal interplay between the receptor and associated Cdk5, by which Cdk5 bound to the receptor C-terminal domain phosphorylates the receptor on Ser350, a necessary step in Cdk5-dependent activation of Cdc42. Bottom, right: the 5-HT7 receptor binds to and activates Cdk5 signaling, a process leading to Tau hyperphosphorylation. APP, amyloid precursor protein.
Figure 4.
Figure 4.. Constitutive activation of 5-HT6 receptors by different GPCR-interacting proteins (GIPs).
Left: The 5-HT6 receptor binds to several proteins of the mammalian target of rapamycin complex 1 (mTORC1) pathway, including mTOR itself and the Ras GTPase-activating protein (Ras-GAP) neurofibromin 1 (NF1). Physical association of NF1 with the receptor strongly enhances constitutive activation of the Gs–adenylyl cyclase pathway by the receptor. Middle: The receptor activates the cyclin-dependent kinase 5 (Cdk5)–Cdc42 signaling pathway in an agonist-independent manner to promote the initiation of neurite growth. Dissociation of the 5-HT6 receptor–Cdk5 complex allows the recruitment of G-protein-regulated inducer of neurite outgrowth 1 (GPRIN1) by the receptor (right panel), which mediates constitutive activation of the Gs–adenylyl cyclase–protein kinase A (PKA) pathway, thereby promoting neurite elongation and branching. *Constitutively active receptor. PI3K, phosphatidylinositol 3-kinase; Ser, serine.
Figure 5.
Figure 5.. Biased signaling at 5-HT2A receptors and 5-HT2A/mGlu2 heteromers.
A. 5-HT2A receptor stimulation by 5-HT activates Gαq and, to a lesser extent, β-arrestin signalling and leads to 5-HT2A receptor desensitization. 5-HT2A receptor stimulation by psychedelic hallucinogens such as lysergic acid diethylamide (LSD), but not by non-hallucinogenic agonists, promotes receptor phosphorylation on serine (Ser)280, a process reducing receptor desensitization. Binding of the receptor to hallucinogenic agonists also stabilizes conformations favoring β-arrestin coupling. Substituting isoleucine181 of the receptor to glutamate suppresses receptor coupling to Gαq while potentiating coupling to β-arrestin upon receptor activation by 5-HT or hallucinogenic agonists. B. Agonist stimulation of metabotropic glutamate receptor 2 (mGlu2) or 5-HT2A receptor within mGlu2–5-HT2A heterodimer promotes mGlu2 receptor phosphorylation on Ser843, which favors engagement of Gαi signaling.
Figure 6.
Figure 6.. Spatiotemporal regulation of 5-HT receptor signaling.
A. Sequential engagement cyclin-dependent kinase 5 (Cdk5)–Cdc42 and Gs–adenylyl cyclase pathways by constitutively active 5-HT6 receptors during neuronal differentiation and dendritic tree morphogenesis. B,C. Difference in coupling properties of 5-HT1A autoreceptor and heteroreceptors and in their propensity to desensitize and internalize upon agonist stimulation. D. Spatiotemporal regulation of 5-HT6 receptor coupling to Gs in neurons. 5-HT6 receptors located in the soma, but not receptors located in the primary cilium, activate cAMP production (in absence or presence of agonist). Upon agonist stimulation, Smoothened (Smo) enters the cilium and inhibits cAMP production by constitutively active GPR161. This favors translocation of active Gli transcription factor (Gli-A) to the nucleus and the transcription of Hedgehog (Hh)-regulated genes. Concomitantly, 5-HT6 receptors located in the primary cilium become able to activate local cAMP production, which might exert a feedback inhibition of Gli-A. *Constitutively active receptors. AC, adenylyl cyclase; GIRK2, G-protein-gated inwardly rectifying potassium channel 2; GPRIN1, G-protein-regulated inducer of neurite outgrowth 1; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; Ptc, patched; Ser, serine; VDCC, voltage-dependent calcium channel.
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Grants and funding

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).

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