title: Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors.
abstract: The serotonin 5-HT(2A) receptor (5-HT(2A)R) and dopamine D(2) receptor (D(2)R) are high-affinity G protein-coupled receptor targets for two different classes of antipsychotic drugs used to treat schizophrenia. Interestingly, the antipsychotic effects are not based on the regulation of same signaling mediators since activation of the 5-HT(2A)R and of the D(2)R regulate G(q/11) protein and G(i/o) protein, respectively. Here we use radioligand binding and second messenger production assays to provide evidence for a functional crosstalk between 5-HT(2A)R and D(2)R in brain and in HEK293 cells. D(2)R activation increases the hallucinogenic agonist affinity for 5-HT(2A)R and decreases the 5-HT(2A)R induced inositol phosphate production. In vivo, 5-HT(2A)R expression is necessary for the full effects of D(2)R antagonist on MK-801-induced locomotor activity. Co-immunoprecipitation studies show that the two receptors can physically interact in HEK293 cells and raise the possibility that a receptor heterocomplex mediates the crosstalk observed. The existence of this 5-HT(2A)R-D(2)R heteromer and crosstalk may have implications for diseases involving alterations of serotonin and dopamine systems and for the development of new classes of therapeutic drugs.
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Albizu
authors.forename: Terrell
authors.initials: T
authors.lastname: Holloway
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D055503:Protein Multimerization / Q000502:physiology*; D020239:Receptor Cross-Talk / Q000502:physiology*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism / Q000502:physiology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D058826:Serotonin 5-HT2 Receptor Agonists