# Direct chemogenetic control of heterotrimeric G protein signaling

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $453,750

## Abstract

ABSTRACT
SIGNIFICANCE: G protein-coupled receptors (GPCRs) initiate cellular responses to many different stimuli, like
neurotransmitters, hormones or photons. They are critical for many physiological processes and their
dysregulation frequently leads to human disease, which is also in agreement with the fact that >30% of FDA-
approved drugs target GPCRs. GPCRs are key pharmacological targets in neurological and neuropsychiatric
diseases based on their function as metabotropic neurotransmitter receptors with a prominent role in
neuromodulation. The main mechanism of action of GPCRs is through activation of heterotrimeric G proteins,
which are broadly divided in 4 families (Gs, Gi/o, Gq/11, G12/13). However, the mechanisms and consequences of
heterotrimeric G protein signaling have been difficult to elucidate because of the lack of adequate experimental
tools to manipulate their activity with high precision and specificity in a cellular context. Our goal is to develop a
new class of chemogenetic tool to directly activate heterotrimeric G proteins without perturbing GPCRs or other
cellular processes. Chemogenetics, in general, refers to a method by which a protein is engineered to interact
with previously unrecognized chemical compounds. The tools to be developed here will allow investigators in
this field of research to manipulate and dissect the functional consequences of G protein activation with
unprecedented precision, thereby revealing fundamental mechanisms that underlie physiological, pathological,
or therapeutic modulation of neurotransmitter responses and other biological processes.
BACKGROUND: Upon stimulation, GPCRs promote GTP loading on the Gα-subunit of heterotrimeric G
proteins (Gαβγ). In turn, Gα-GTP binds to effector proteins to propagate signaling. In the context of
neurotransmission, Gα proteins of the Gs (e.g., Gαs) or the Gq/11 (e.g., Gαq) family are primarily
neurostimulatory by virtue of their ability to increase cAMP or intracellular Ca2+, respectively. In contrast, Gα
proteins of the Gi/o family (e.g., Gαi) cause neuroinhibition via suppression of cAMP. These effects are
mediated through direct binding to and modulation of effector proteins that control second messenger levels—
i.e., adenylyl cyclases for Gαs and Gαi, or phospholipases C for Gαq. Gβγ also contributes to neuromodulation
through the regulation of ion channels. We have envisioned and partially validated a chemogenetic approach
to achieve the direct and specific activation of G proteins without the need of GPCRs.
SYNOPSIS OF AIMS: In Aim 1, we will identify the components required to engineer Gαi, Gαs, Gαq, or Gβγ
proteins that are activated by chemical compounds that do not have known targets or effects in mammalian
cells. These constructs will be evaluated by using optical biosensors that directly detect active G proteins. In
Aim 2, we will test the performance of these chemically-activated G proteins by using downstream signaling
readouts directly dependent ...

## Key facts

- **NIH application ID:** 10590217
- **Project number:** 1R21NS127065-01A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Mikel Garcia-Marcos
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $453,750
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10590217

## Citation

> US National Institutes of Health, RePORTER application 10590217, Direct chemogenetic control of heterotrimeric G protein signaling (1R21NS127065-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10590217. Licensed CC0.

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