Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A{middle dot}mGlu2) receptor heteromerization and its psychoactive behavioral function

Moreno, J.L. et al. (2012) Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A{middle dot}mGlu2) receptor heteromerization and its psychoactive behavioral function. Journal of Biological Chemistry, 287(53), pp. 44301-44319. (doi: 10.1074/jbc.M112.413161)

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Abstract

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-hydroxytryptamine 2A (5-HT2A) receptor in the mouse frontal cortex. Substitution of these residues (Ala-6774.40, Ala-6814.44, and Ala-6854.48) leads to absence of 5-HT2A·mGlu2 receptor complex formation, 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. Furthermore, the ligand binding interaction between the components of the 5-HT2A·mGlu2 receptor heterocomplex is up-regulated in the frontal cortex of schizophrenic subjects as compared with controls. Together, these findings provide structural evidence for the unique behavioral function of a GPCR heteromer.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lopez-Gimenez, Dr Juan and Milligan, Professor Graeme
Authors: Moreno, J.L., Muguruza, C., Umali, A., Mortillo, S., Holloway, T., Pilar-Cuellar, F., Mocci, G., Seto, J., Callado, L.F., Neve, R.L., Milligan, G., Sealfon, S.C., Lopez-Gimenez, J.F., Meana, J.J., Benson, D.L., and Gonzalez-Maeso, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:0021-9258
Published Online:05 October 2012

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