# The role of RGS12 in differential modulation of G protein versus beta-arrestin signaling downstream of the kappa opioid receptor

> **NIH NIH R01** · UNIVERSITY OF NORTH TEXAS HLTH SCI CTR · 2022 · $359,793

## Abstract

The kappa opioid receptor (KOR) helps mediate responses to stress, yet is also implicated in developing and/or
maintaining health disorders of chronic pain, drug addiction, anxiety and depression. KOR agonists have shown
promise in ameliorating these disorders, but are limited by dysphoric side effects. Beneficial effects of KOR
agonists (e.g., analgesia) are considered predominantly mediated by G protein signaling, whereas β-arrestin
signaling is considered central to their detrimental side effects (e.g., dysphoria). However, the mechanism(s)
by which these signals downstream of KOR are regulated are still being elucidated. The Regulators of
G protein Signaling are intracellular proteins that accelerate signal termination after G protein-coupled receptor
activation. RGS12 is a complex member of this protein family, with at least five different domains that interact
with components of both G protein-dependent and -independent signaling pathways. We recently reported that
RGS12 is enriched in the ventral striatum (vSTR), and global Rgs12 ablation decreases locomotor responses to
dopamine (DA)-modulating psychostimulants. Our data correlate with the augmented DA transporter (DAT)
expression and function in the vSTR, but not dorsal striatum (dSTR), seen in RGS12-null mice. Loss of RGS12
(especially as a Gai/o-directed GTPase-accelerating protein) may indirectly increase DAT expression / function
by removing negative regulation downstream of KOR, given that KOR agonists are known to increase DAT
surface expression and uptake function. Supporting this notion, the augmented DAT function and reduced
AMPH-stimulated locomotion caused by RGS12 loss are both reversed following KOR antagonism. We also
found elevated KOR expression in the vSTR, but not dSTR, of RGS12-null and β-arrestin2-null mouse strains.
RGS12 over-expression augments β-arrestin recruitment to activated KOR – an effect preserved following
pertussis toxin-mediated Gi/o inhibition or mutation to the Ga-interacting domains of RGS12, suggesting a
G protein-independent mechanism. These findings are consistent with our newest data that RGS12-null mice
exhibit attenuated KOR agonist-induced conditioned place aversion, considered β-arrestin-dependent behavior.
Collectively, our data highlight a role for RGS12 as a novel, differential regulator of both G protein-dependent
and -independent signaling downstream of KOR activation, a regulation that may be exploitable
pharmacologically to help shift KOR-mediated signaling to beneficial outcomes and away from detrimental ones.
Our first aim is to determine the specific neuronal populations within which RGS12 acts to modulate G protein-
dependent and -independent KOR signaling, testing hypotheses that RGS12 operates to modulate KOR and
DAT function specifically in KOR- and DAT- expressing CNS neurons, and also operates at the level of the spinal
cord. Our second aim is to delineate the molecular determinants that engender selective functional interactio...

## Key facts

- **NIH application ID:** 10348646
- **Project number:** 5R01DA048153-02
- **Recipient organization:** UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
- **Principal Investigator:** David P. Siderovski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $359,793
- **Award type:** 5
- **Project period:** 2021-02-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348646

## Citation

> US National Institutes of Health, RePORTER application 10348646, The role of RGS12 in differential modulation of G protein versus beta-arrestin signaling downstream of the kappa opioid receptor (5R01DA048153-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10348646. Licensed CC0.

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