# Structure and Function of Dopamine Receptors

> **NIH NIH R01** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2022 · $701,571

## Abstract

Dopamine D2 receptors, the targets of all antipsychotic drugs currently available, have been reported to form
dimeric and/or oligomeric complexes with many other receptors. These complexes and their functional properties
are of great interest given the possibility of developing novel therapeutics that selectively target distinct receptor
complexes, with the potential of reduced side-effects. Nevertheless, there is still great debate about whether
these and other class A G protein-coupled receptor (GPCR) complexes even exist, as well as their potential
physiological relevance. Of the methods capable of detecting receptor interactions in living cells, single-molecule
imaging techniques offer the distinct advantage of potentially revealing the stochastic and dynamic behaviors of
individual molecules in real time, without the population and time averaging inherent in ensemble measurements.
Specifically, single-molecule fluorescence resonance energy transfer (smFRET) is a robust tool for reporting
interaction distances less than 10 nm, but has rarely been used in mammalian cells, and never with GPCRs, due
to multiple experimental challenges. We have now developed robust methods for imaging, tracking, and
quantifying smFRET of GPCRs in living cells. In parallel, using pulsed-interleaved excitation fluorescence cross-
correlation spectroscopy (PIE-FCCS) we can robustly explore interactions at much higher levels of receptor
expression. While we find that the class A mu opioid receptor is a monomer over a 1000-fold range of receptor
expression, our preliminary results show that the D2R does in fact transiently interact in the membrane when
expressed at high densities. Furthermore, using PIE-FCCS we see strong evidence for heteromeric interactions
of D2R and adenosine A2A receptor, a heteromeric pair shown to exhibit substantial functional crosstalk. We
propose to study the dynamics of these interactions and to identify modulators of their kinetics, as tools to probe
the potential role of homodimers and heterodimers in vivo. We will also extend our studies to the D2R-NMDA
receptor (NMDAR) heteromer, a complex that we have now shown to be upregulated both in rodent and human
brain exposed to psychostimulants that elevate extracellular dopamine levels. Although the mechanism is
unknown, there is evidence that D2R activation leads through increased D2R-NMDAR to inhibition of NMDAR
currents and reduced neuronal excitability, suggesting a novel molecular target for integration of dopamine
signaling and glutamatergic signaling, both of which have been implicated in schizophrenia and psychosis.
 We thus propose the following specific aims to expand our lab’s ongoing multi-level approach to
understanding dopamine receptor structure and function both in vitro and in vivo. Aim 1: Determine the dynamics
of dopamine D2R homo- and Class A GPCR hetero-dimerization in living cells and in brain slices and identify
modulators of these dynamics to probe their functional eff...

## Key facts

- **NIH application ID:** 10440536
- **Project number:** 5R01MH054137-24
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Jonathan A Javitch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $701,571
- **Award type:** 5
- **Project period:** 1995-09-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440536

## Citation

> US National Institutes of Health, RePORTER application 10440536, Structure and Function of Dopamine Receptors (5R01MH054137-24). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10440536. Licensed CC0.

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