5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling

Abstract

The serotonin 5-HT and glutamate mGlu receptors continue to attract particular attention, given their implication in psychosis associated with schizophrenia and the mechanism of action of atypical antipsychotics and a new class of antipsychotics, respectively. A large body of evidence indicates a functional crosstalk between both receptors in the brain, but the underlying mechanisms are not entirely elucidated. Here, we have explored the influence of 5-HT receptor upon the phosphorylation pattern of mGlu receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser was enhanced upon mGlu receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT receptor. Likewise, administration of LY379268 increased mGlu receptor phosphorylation at Ser in prefrontal cortex of wild-type mice but not 5-HT mice. Exposure of HEK-293 cells co-expressing mGlu and 5-HT receptors to 5-HT also increased Ser phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser phosphorylation elicited by 5-HT receptor stimulation was prevented by the mGlu receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT receptor antagonist M100907. Mutation of Ser into alanine strongly reduced G signaling elicited by mGlu or 5-HT receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu receptor phosphorylation at Ser as a key molecular event that underlies the functional crosstalk between both receptors.

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…Although in that study it was not possible to unequivocally determine the molecular events leading to the specific phosphoproteomics changes observed, one potential explanation could be that the psychedelicstabilized 5-HT 2A receptor conformation might modulate protein kinase C access, leading to a psychedelicspecific phosphorylation fingerprint (Karaki et al, 2014). Interestingly, it was also reported that mGluR2 undergoes specific ligand-induced phosphorylation at Ser 843 only in the presence of 5-HT 2A receptor, which could represent a key molecular interaction mediating the psychedelic crosstalk between these two receptors and might be involved in psychedelic-initiated therapeutic improvements (Murat et al, 2019). Whether psychedelics affect 5-HT 2A receptor-mediated mGluR2 phosphorylation remains to be ascertained.…”

“…Furthermore, an allosteric interaction of 5-HT 2A and mGlu2 receptors has not been independently replicated in any other laboratory. They conclude that until ultrastructural studies can be finalized, the physiological importance of a 5-HT 2A -mGlu2 heterodimer remains questionable and controversial (Nichols, 2016;Murat et al, 2019).…”

International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

“…Interestingly, mGlu 2 , but not mGlu 3 , receptors are reportedly resistant to homologous desensitization by G protein-coupled receptor kinases with respect to cAMP signaling (Iacovelli et al, 2009), although heterologous mechanisms, for example, due to PKC activation by colocated adenosine A 3 receptors, affect both subtypes (Macek et al, 1998;Lennon et al, 2010). Functional cross-talk between mGlu 2 receptors and colocated serotonin receptors 2A (5-HT 2A ) can also modulate cellular responses to activation of either receptor (Marek et al, 2000;Molinaro et al, 2009;Murat et al, 2019). The interplay of intracellular effectors stimulated by group II mGlu receptors, coupled with regulatory proteins as well as coexpression of Metabotropic Glutamate Receptors other cell surface receptors, gives rise to cell typespecific roles for group II mGlu receptors.…”

Metabotropic Glutamate Receptor Trafficking and its Role in Drug-Induced Neurobehavioral Plasticity

“…It should be noted that both groups I and group II/III receptors can also modulate G-protein independent signaling pathways [25,26], adding additional complexity to mGlu-dependent regulation of cellular signaling and synaptic plasticity. Emerging evidence suggests that these non-canonical signaling pathways can also provide feedback regulation of mGlu function through post-translational modification and trafficking [27][28][29][30][31]. While the dysregulation of mGluRs has been linked to a variety of neurological and psychiatric disorders, the role of mGluR membrane trafficking in these disorders remains poorly understood.…”