# Nonconventional role of ADCY in Gq-mediated neuronal signaling and neuroplasticity

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2022 · $448,129

## Abstract

This project will delineate a non-conventional role of adenylyl cylcase (ADCY) in regulating Gq-mediated
signaling and synaptic long-term depression LTD (LTD) in normal brain and pathophysiology associated with
Fragile X syndrome (FXS). Activation of specific groups of G protein-coupled receptors stimulates Gq, and in
turn triggers signal transduction cascade, leading to translation-dependent synaptic plasticity such as LTD.
Relevant to neurological disorders, hyper-function of Gq-coupled metabotropic glutamate receptor 5 (mGluR5)
and muscarinic acetylcholine receptor (Gq-mAchR) as well as elevated translation underlie multiple aspects of
neuronal dysfunction in FXS. We recently found that type 1 adenylyl cylcase (ADCY1) level is aberrantly
increased in FXS mouse model (i.e. Fmr1 knockout mice). Genetic deletion or pharmacological inhibition of
ADCY1 corrects core cellular and behavioral symptoms. Intriguingly, inconsistent with the current
understanding on Gq, of which the functions of ADCY and cAMP-mediated signaling are not considered,
we found that ADCY1 is essential for LTD following activation of mGluR5. Based on these results, our
central hypothesis is that the Ca2+-stimulated ADCY1 is a functional component of Gq signaling, and thereby
the abnormally elevated ADCY1 expression in FXS accounts for the exaggerated Gq-mediated synaptic
dysfunction and aberrantly elevated translation. This project will first address how ADCY1 regulates Gq
signaling, translation, and Gq-LTD in normal neurons. Second, it will address how elevated ADCY1 governs
alterations in distinct translation process, and whether elevated ADCY1 is causal for Gq-mediated synaptic
dysfunction in FXS neurons. Considering that the conventional view emphasizes the role of PLC
(phospholipase C)-Ca2+/PKC (protein kinase C) cascade rather than ADCY/cAMP in Gq signaling, validation of
ADCY1 function in Gq-mediated signaling and Gq-LTD will suggest a substantial paradigm shift/modification
and re-define how Gq functions in neurons. The results of this project will also provide new insights into
pathophysiology and disease mechanism in FXS. It will reveal that ADCY1, as a key target of FMRP (Fragile X
mental retardation protein), connects altered Gq signaling cascades with abnormal translation and synaptic
dysfunction in FXS. It will uncover a new concept that the abnormal ADCY1-mediated signaling contributes to
altered global translation via distinct aspects of translation processes such as translation capacity and
efficiency, and thereby advance our understanding on FXS pathology. Considering that ADCY1 is only
expressed in the central nervous system and functionally connected to multiple signaling molecules that are
altered in FXS, the results will also suggest an attractive and mechanism-based therapy.

## Key facts

- **NIH application ID:** 10338100
- **Project number:** 5R01MH119149-04
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Hongbing Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $448,129
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10338100

## Citation

> US National Institutes of Health, RePORTER application 10338100, Nonconventional role of ADCY in Gq-mediated neuronal signaling and neuroplasticity (5R01MH119149-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10338100. Licensed CC0.

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