Decoding the signaling of the D2R-2AR heteromer: relevance to schizophrenia

Author

Miao HuangFollow

DOI

https://doi.org/10.25772/JYPT-DP81

Defense Date

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Diomedes E. Logothetis

Abstract

Schizophrenia is a severe mental disorder affecting ~1% of world population. Two G protein coupled receptors (GPCRs): Gi-coupled dopamine D2 receptor (D₂R), and Gq-coupled serotonin 2A receptor (2AR), are targeted by the typical and atypical antipsychotic drugs to treat schizophrenia. These two receptors have been shown to co-localize in brain regions relevant to schizophrenia, including the ventral tegmental area (VTA), striatum, and prefrontal cortex (PFC). Studies in our lab characterized the integrated signaling of the D₂R-2AR heteromer and found that both the Gi activity of D₂R and the Gq activity of 2AR were potentiated in response to dopamine (DA) and serotonin (5-HT), whereas the potency of the typical antipsychotic drug (APD) haloperidol antagonizing Gi and Gq signaling was also enhanced. Using a peptide mimicking the transmembrane (TM) domain 5 of D₂R, we showed disruption of the formation and function of the D₂R-2AR heteromer in heterologous systems and ex vivo brain slices. Our functional and mutagenesis data suggested that D₂R and 2AR heteromerize though a symmetric TM5,6-TM5,6 interface, and a network of Pi-Pi stacking interaction among eight conserved aromatic residues of D₂R and 2AR may underlie the mechanism for the functional cross-talk between D₂R and 2AR. Based on these results, we built a structural model for the D₂R-2AR heteromer recapitulating its functional cross-talk characteristics. We are presently pursuing behavioral experiments to investigate the effectiveness of antipsychotic drugs on the function of the D₂R-2AR heteromer in animal models of psychosis. Our overall study shows a dual role of the D₂R-2AR heteromer in schizophrenia-associated psychosis and sheds light on the development of future therapeutic drugs for schizophrenia and other psychotic diseases.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-14-2018