Diversity and bias through dopamine D2R heteroreceptor complexes

•Diversity and bias develop in GPCR dimers through allosteric receptor interactions.•The D2R is a hub receptor forming multiple heteroreceptor complexes.•In A2AR-D2R complexes the D2R protomer is biased towards β-arrestin2 signaling.•In D2R-5-HT2AR complexes hallucinogenic 5-HT2A agonists induce a biased 5-HT2AR.•Bias and diversity in D2R protomers offer a promised land for drug development.

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.

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