title: Diversity and bias through dopamine D2R heteroreceptor complexes.
abstract: The D2R is a hub receptor interacting with a large number of other GPCRs. A2AR activation of the antagonistic A2AR-D2R interaction not only leads to inhibition of the Gi/o signaling but also to an increase in β-arrestin2 signaling over the D2R protomer. Hallucinogenic 5-HT2AR agonists can produce a biased agonist state at the 5-HT2AR protomer of D2R-5-HT2AR heteroreceptor complexes with increased D2R recognition and Gi/o mediated signaling. Allosteric receptor-receptor interactions in D2-NTR1 heteroreceptor complexes inhibit D2R function and can switch G protein coupling. These large numbers of D2R heterocomplexes and their allosteric receptor-receptor interactions produce a marked increase in diversity and bias of the participating D2R protomers opening a promised land for drug development in schizophrenia, addiction and Parkinson's disease.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden; Department of Biomolecular Science, Section of Physiology, University of Urbino, Campus Scientifico Enrico Mattei, via Ca' le Suore 2, I-61029 Urbino, Italy; Observatorio Cubano de Neurociencias, Grupo Bohío-Estudio, Zayas 50, 62100 Yaguajay, Cuba.
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden. Electronic address: kjell.fuxe@ki.se.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D000494:Allosteric Regulation; D015195:Drug Design; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy / Q000503:physiopathology; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018028:Receptors, Neurotensin / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D015398:Signal Transduction; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D043705:Receptor, Adenosine A2A; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor