Diversity and bias through dopamine D2R heteroreceptor complexes

Curr Opin Pharmacol. 2017 Feb:32:16-22. doi: 10.1016/j.coph.2016.10.004. Epub 2016 Nov 11.

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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Drug Design*
  • Humans
  • Parkinson Disease / drug therapy
  • Parkinson Disease / physiopathology
  • Receptor, Adenosine A2A / metabolism
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Neurotensin / metabolism
  • Schizophrenia / drug therapy
  • Schizophrenia / physiopathology
  • Signal Transduction
  • Substance-Related Disorders / drug therapy
  • Substance-Related Disorders / physiopathology

Substances

  • Receptor, Adenosine A2A
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • Receptors, G-Protein-Coupled
  • Receptors, Neurotensin
  • neurotensin type 1 receptor