# RGS2 regulation of D2 receptor signaling

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $291,366

## Abstract

Project Summary
The overall goal of this project is to increase our understanding of neurobiological signaling process that
mediates physiological and behavioral effects of dopamine. This proposal focuses on a novel regulation of
dopamine D2 autoreceptor (D2AR) signaling in the midbrain by RGS2 (regulator of G protein signaling 2)
proteins. Dysfunctional midbrain D2AR is implicated in neurological and psychiatric diseases. However, little
knowledge is known about the mechanisms of midbrain D2AR signaling. D2R signals via its coupled Gαi/o
protein to mediate cellular and behavioral responses to stimuli. The family of RGS proteins is a key negative
modulator of D2R signaling by accelerating GTP hydrolysis and terminating G protein signaling. To date, no
study has examined the associations between specific RGS proteins and D2AR signaling in midbrain
dopaminergic neurons. We find that amphetamine self-administration increases RGS2 protein levels and
decreases D2R-stimulated G protein activation in rat midbrain. Moreover, RGS2 and D2AR are both expressed
in midbrain dopaminergic neurons. Thus, RGS2 and D2AR may be functionally linked. Using neuroblastoma
N2A cells as a model system, we made a novel observation that RGS2 negatively regulates D2R-mediated
Gαi/o signaling. Moreover, RGS2 couples with D2R via its N-terminus. Thus, we hypothesize that RGS2
directly interacts with D2R to engage a unique Gαi/o signaling pathway that controls physiological and
behavioral responses of D2AR in midbrain dopaminergic neurons. This hypothesis will be tested in two specific
aims: 1) assess whether RGS2 directly interacts with D2R to control D2R-mediated G protein signaling in N2A
cells; and 2) determine the physiological and behavioral significance of the RGS2-D2AR interaction in
dopaminergic neurons of ventral tegmental area. This proposal has a potential to identify RGS2 as a novel
therapeutic target of the D2R signaling in vivo.

## Key facts

- **NIH application ID:** 9979825
- **Project number:** 5R01DA042862-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Rong Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $291,366
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979825

## Citation

> US National Institutes of Health, RePORTER application 9979825, RGS2 regulation of D2 receptor signaling (5R01DA042862-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9979825. Licensed CC0.

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