Novel and atypical pathways for serotonin signaling

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.

Trauma and Remembering: From Neuronal Circuits to Molecules

“…Surprisingly, MDMA also activates sigma-1 receptors with a behavioral effect similar to DMT in animal models [79]. In conclusion, serotonergic and dissociative (NMDAantagonist) psychedelics act in cooperation at the cellular level [74]. These mechanisms are highly relevant in PTSD.…”

“…5-HT2A agonism is a common mechanism of serotonergic psychedelics, including psilocybin ("magic mushroom", 4-phosphoryloxy-N, N-dimethyltryptamine) and Ayahuasca (N,N-dimethyltryptamine, DMT) [60]. Lysergic acid diethylamide (LSD) is only a partial agonist on 5-HT2A, promoting beta-arrestin activation and slow receptor desensitization, but a full agonist at 5-HT1A and several dopamine receptors (D1, D2, and D4) [53,74].…”

“…Moreover, 5-HT2A receptors form dimers with type 2 metabotropic glutamate receptors (mGlu2), together with other G-protein coupled receptors [82] (Figure 2). The serotonin-glutamate receptor complex induces the phosphorylation of the mGlu2 receptor on a serine residue (Ser843) when 5-HT2A is stimulated by psychedelics [74]. This receptor crosstalk represents a direct interaction between the serotonin and glutamate systems to boost the synthesis of new proteins in the synapses and enhance memory reconsolidation.…”

“…These dimers operate via both Gq and Gi proteins. 5-HT-glutamate activations enhance CAMPKII via Gq proteins, whereas they inhibit cAMP-PKA via Gi proteins [74,82]. Both mechanisms contribute to the activation of scaffolding protein degradation at the proteasomes and the consequent destabilization of engrams [53,74,83].…”

Metagenomic-Metabolomic Mining of Kinema, a Naturally Fermented Soybean Food of the Eastern Himalayas

“…Pantothenate and pyridoxamine were positively correlated with B. subtilis strain, which may enhance the biosynthesis of vitamins and cofactors in kinema, imparting health-promoting benefits to consumers. Serotonin, a neurotransmitter (Sahu et al, 2018), was found to be correlated with the neuroactive ligandreceptor interaction via predictive function, and it could control the signaling pathways either intracellularly by serotonylation or extracellularly via membrane receptors (Bockaert et al, 2021). Swainsonine predicted in KEGG database was also detected in metabolomics analysis in kinema samples, which is involved in the biosynthesis of tropane, piperidine, and pyridine alkaloid (Li and Lu, 2019).…”