Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades

Psychedelics

“…Fribourg et al (2011) further extended the original findings presented by González-Maeso et al (2008). Delille et al (2012) subsequently coexpressed mGlu2 receptors in an inducible manner in a constitutive 5-HT 2A background in HEK-293 cells. They determined the reciprocal influence of the two receptors on receptor expression and measured intracellular Ca +2 as well as cAMP levels after stimulation with agonists, antagonists, psychedelics, and positive allosteric modulators.…”

“…In addition, psychedelic 5-HT 2A agonists had no effect on G ai -mediated signaling. The results of Delille et al (2012) indicate that the functional interaction of mGlu2 and 5-HT 2A receptors may not be mediated by heterodimer interaction.…”

The Prevalence, Maintenance, and Relevance of G Protein–Coupled Receptor Oligomerization

“…Moreover, this effect is restored in such animals by virally mediated reintroduction of the mGluR2 receptor . A series of studies have shown the capacity of these two otherwise unrelated GPCRs to interact and form a functional complex in both cellular systems and the brain (González-Maeso et al, 2008;Delille et al, 2012), whereas a range of other studies have also shown pharmacological interactions between these receptors (e.g., Molinaro et al, 2009). A key element of the studies by González-Maeso et al (2008), which was extended by further studies by Fribourg et al (2011), was the alteration in signal transduction pathways produced via this heteromer.…”

“…A key element of the studies by González-Maeso et al (2008), which was extended by further studies by Fribourg et al (2011), was the alteration in signal transduction pathways produced via this heteromer. It must be noted that not all studies have been able to replicate the reported changes in ligand pharmacology and signaling (Delille et al, 2012), but further recent studies from González-Maeso and colleagues used chimeric mGluR2/mGluR3 constructs and variation in sequence at the cytoplasmic end of transmembrane domain IV between these closely related receptors to define a small number of residues of mGluR2 that, when mutated to the equivalent sequence of mGluR3, greatly reduced interactions with the 5-HT 2A receptor. When a mutant mGluR2 containing three such amino acid changes was introduced into mGluR2 knockout mice, unlike wild-type mGluR2, this construct was unable to restore the head-twitch response produced by 2,5-dimethoxy-4-iodoamphetamine.…”

Promiscuous Dimerization of the Growth Hormone Secretagogue Receptor (GHS-R1a) Attenuates Ghrelin-mediated Signaling

“…This serotonin-mediated attenuation of ghrelin signaling may potentially involve dimerization of the GHS-R1a and the 5-HT 2C receptor, which is a previously unexplored possibility under investigation here. Notably, serotonin receptors have been found to exist as oligomer complexes with other serotonin receptor family members (51), with metabotrophic glutamate receptors (52)(53)(54), and with dopamine receptors (55). However, oligomeric complex formation does not always translate into second messenger signaling effects, because downstream consequences were unaffected in a 5-HT 2A /mGlu 2 heterocomplex (54).…”