J Biol Chem. 2012 Nov 5. [Epub ahead of print]
Identification of Three Residues Essential for 5-HT2A-mGlu2 Receptor Heteromerization and its Psychoactive Behavioral Function.
Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuellar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, Lopez-Gimenez JF, Meana JJ, Benson DL, Gonzalez Maeso J.
Mount Sinai School of Medicine, United States
Serotonin and glutamate G protein-coupled receptor (GPCR) neurotransmission affects cognition and perception in humans and rodents. GPCRs are capable of forming heteromeric complexes that differentially alter cell signaling, but the role of this structural arrangement in modulating behavior remains unknown. Here we identified three residues located at the intracellular end of transmembrane domain four that are necessary for the metabotropic glutamate 2 (mGlu2) receptor to be assembled as a GPCR heteromer with the serotonin 5-HT2A receptor in mouse frontal cortex. Substitution of these residues (A6774.40, A6814.44 and A6854.48) leads to absence of molecular proximity between 5-HT2A and mGlu2, an effect that is associated with a decrease in their heteromeric ligand binding interaction. Disruption of heteromeric expression with mGlu2 attenuates the psychosis-like effects induced in mice by hallucinogenic 5-HT2A agonists. Further, the allosteric functional crosstalk between the components of the 5-HT2A-mGlu2 receptor heterocomplex is up-regulated in frontal cortex of schizophrenic subjects as compared to controls. Together, these findings provide structural evidence for the unique behavioral function of a GPCR heteromer. |
