# Molecular basis for GPCR signaling fine-tuning in neurons

> **NIH NIH F31** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $46,752

## Abstract

SIGNIFICANCE: G protein-coupled receptors (GPCRs) activate heterotrimeric G proteins, which together form
one of the most important signaling axes found in the cell. Because GPCRs are very common targets for
therapeutic drugs, the mechanisms that underlie their regulation are of high biomedical importance. Although it
is known that many cytoplasmic factors regulate the activity of G proteins after GPCR-mediated activation, they
remain greatly understudied as an untapped opportunity for therapeutic intervention. My goal here is to
characterize a novel cytoplasmic regulator of G proteins that operates through modulation of
neurotransmission, and has been shown to be relevant in the context of neurological disorders including
chronic pain and epilepsy. Current treatments for these diseases include addictive opioids in the case of pain,
or a trial-and-error drug seeking process for epilepsy that still leaves approximately 1/3 of patients with
ineffective treatments. For this reason, in this proposal I will study the molecular mechanism by how this novel
regulator controls GPCR-G protein neuronal signaling. Elucidating the molecular mechanisms of this
physiologically important G protein regulator is a first step towards the development of novel targeted
treatments for diseases that arise from dysregulated GPCR signaling.
BACKGROUND: In the course of a screen for G protein activators that bind to Gαi subunits, my Sponsor's
laboratory identified a protein that regulates G proteins via a unique and novel mechanism. We coined the term
“paradoxical G protein regulator” (PGR) to convey that it upregulates the modulation of some G protein
effectors while simultaneously downregulating the modulation of other G protein effectors. Others had found
that loss of this “PGR” alters GPCR signaling in neurons of the peripheral nervous system and causes chronic
pain. More recently my Sponsor's laboratory has found that PGR KO mice also have increased seizure
susceptibility. Despite its clear biomedical importance, the molecular mechanisms by which this G protein
regulator operates, and whether it modulates neurotransmission in brain neurons are completely unknown.
SYNOPSIS OF AIMS: Based on compelling preliminary data, I propose that the PGR modulates both Gαi- and
Gβγ-dependent signaling without directly affecting the G protein enzymatic activity (i.e., nucleotide binding
and/or hydrolysis), and that this novel mechanism fine tunes GPCR signaling in brain neurons. In AIM#1 I will
dissect how the PGR regulates G protein signaling in reconstituted systems (in vitro and cell-based), whereas
in AIM#2 I will characterize how it engages physically Gαi by combining mass-spectrometry and mutagenesis.
In AIM#3 I will characterize how the endogenous PGR regulates neuronal GPCR signaling by using primary
cultures of neurons from wild-type and KO mice. Together, the achievement of my goals will lead to the
dissection of a previously uncharacterized mechanism of regulation of GPC...

## Key facts

- **NIH application ID:** 10329942
- **Project number:** 5F31NS115318-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Alex Luebbers
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329942

## Citation

> US National Institutes of Health, RePORTER application 10329942, Molecular basis for GPCR signaling fine-tuning in neurons (5F31NS115318-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10329942. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*