Identification of Three Residues Essential for 5-Hydroxytryptamine 2A-Metabotropic Glutamate 2 (5-HT2A·mGlu2) Receptor Heteromerization and Its Psychoactive Behavioral Function

Abstract

Background:The 5-HT 2A ⅐mGlu2 receptor heterocomplex is involved in psychosis.

Inhibition of melanocortin-4 receptor dimerization by substitutions in intracellular loop 2

“…In conclusion, the conformation and interplay of the entire intracellular TMH3-ICL2-TMH4 region is a regulating element in signaling and receptor organization. Our findings add to the few known examples of GPCR dimer dissociation induced by ligand binding or mutations (Grant et al 2004, Ravindran et al 2009, Moreno et al 2012.…”

“…There have only been a few reports (Grant et al 2004, Ravindran et al 2009, Moreno et al 2012 of GPCR dimer dissociation induced by ligand binding or mutations. Single side chain substitutions have been found to interrupt the dimer interface at TMH4, as in chemokine receptor CCR5 (one residue) or the heterodimer between the metabotropic glutamate-2 receptor and Dimerization of the chimeric MC4R/CB1R receptors.…”

Repressive Epigenetic Changes at themGlu2Promoter in Frontal Cortex of 5-HT2AKnockout Mice

“…For HSV-FLAG-Egr1, the FLAG-Egr1 fragment was digested from pcDNA3.1-FLAG-Egr1 (see cloning above) and subcloned into the BamH1 and XhoI sites of the bicistronic p10051 HSV plasmid expressing green fluorescent protein (GFP) under the control of the CMV promoter (Kurita et al, 2012). The pcDNA3.1-c-Myc-5HT2A plasmid and the mGlu2 promoter construct have been previously described (Kurita et al, 2012;Moreno et al, 2012). All the constructs were confirmed by DNA sequencing.…”

“…FLAG-Egr1 was subcloned into a published bicistronic HSV-GFP virus vector (see above), and viral particles were then packaged as described before (Kurita et al, 2012). HSV-FLAG-Egr1, or control HSV-GFP, was injected into the frontal cortex by stereotaxic surgery according to standard methods (Kurita et al, 2012;Moreno et al, 2012). In brief, mice were anesthetized with a combination of ketamine (100 mg/kg) and xylazine (10 mg/kg) during the surgery.…”

“…Previous findings convincingly demonstrate a functional interaction between 5-HT 2A and metabotropic glutamate 2 (mGlu2) receptors in vitro and in rodent models. Thus, drugs that activate the mGlu2 modulate the cellular (Zhai et al, 2003;Benneyworth et al, 2007;Gonzalez-Maeso et al, 2008;Moreno et al, 2011a), electrophysiological Fribourg et al, 2011;Kurita et al, 2012), and behavioral (Gewirtz and Marek, 2000;Benneyworth et al, 2007;Moreno et al, 2011aMoreno et al, , 2012 responses that require expression of the 5-HT 2A receptor in cortical neurons. Of interest, we previously reported that 5-HT 2A -KO mice show reduced cortical expression of mGlu2 mRNA (Gonzalez-Maeso et al, 2008), which further supports the cross-modulation of a diverse array of functions between 5-HT 2A and mGlu2 receptors.…”