# G alpha Z subunit as a potential therapeutic target to modulate mu opioid receptor pharmacology

> **NIH NIH R21** · UNIVERSITY OF ROCHESTER · 2022 · $423,500

## Abstract

Project Summary/Abstract
The goal of this study is to determine the role of Gαz signaling in modulating opioid pharmacology.
To produce a wide variety of cellular responses, all G protein coupled receptors (GPCRs) couple to
heterotrimeric G proteins to serve as the intermediaries between the receptor and downstream effectors.
There are 16 different Gα subunits, five Gβ, and 12 Gγ subunits. Because of the number of G protein
subunits, there are numerous possible trimer combinations. Gα proteins control signal duration by binding
to either GDP or GTP. Opioid receptors (ORs) predominately couple to the Gαi/o class, comprised of Gαi1,
Gαi2, Gαi3, GαoA, GαoB, and Gαz.
Previous studies showed that mice lacking Gαz had an accelerated rate of morphine antinociceptive
tolerance development. Knockout of the regulator of G protein signaling (RGS), RGSz1, increased Gαz
signaling, and increased the analgesic efficacy of MOR agonists in mice and delayed the development of
morphine tolerance. Collectively, enhancing signaling through Gαz increases morphine analgesic efficacy
and reduces the development of morphine tolerance.
Our preliminary published studies, using bioluminescence resonance energy transfer (BRET) and HEK
293T cells transfected with the κ opioid receptor (KOR), showed differential potency and efficacy of κ
opioid agonists when the KOR signaled through different Gα subunits. When the KOR signaled through
Gαz, opioid agonists, particularly partial agonists, were more potent and sometimes more efficacious than when
the KOR signaled through other Gα subunits. Our hypothesis is that µ opioid agonists signaling through
the MOR coupled to Gαz will be more potent and sometimes more efficacious than when the MOR signals
through other Gαi/o subunits. By understanding how opioid pharmacology is affected by the MOR signaling
through Gαz in comparison to other Gα subunits from the Gαi/o family, it may be possible to design therapeutics
to increase or decrease signaling of the MOR through Gαz, thereby increasing or decreasing the potency and
efficacy of µ opioid agonists. The following Specific Aims will be investigated using a BRET assay to measure
receptor activation and steady-state conditions. 1) Mu opioid agonists will be tested for efficacy and potency
with the MOR signaling through the Gαz subunit and results will be compared with signaling through
other Gα subunits. When the MOR is signaling through Gαz, the simple classification of opioids as full or partial
agonists or antagonists may be changed. 2) Studies will determine the effect of RGSZ, which is RGS20, on
activation and deactivation kinetics and to determine if RGSZ affects opioid efficacy and potency when
the MOR is signaling through Gαz. Collectively, these experiments will determine if MOR signaling through
Gαz changes MOR pharmacology, and if increasing or decreasing Gαz activity is a potential therapeutic target.

## Key facts

- **NIH application ID:** 10580415
- **Project number:** 1R21DA057500-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** JEAN M BIDLACK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,500
- **Award type:** 1
- **Project period:** 2022-09-30 → 2025-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10580415

## Citation

> US National Institutes of Health, RePORTER application 10580415, G alpha Z subunit as a potential therapeutic target to modulate mu opioid receptor pharmacology (1R21DA057500-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10580415. Licensed CC0.

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