# Molecular Regulation of Metabotropic Glutamate Receptors in Striatal Neurons

> **NIH NIH R01** · UNIVERSITY OF MISSOURI KANSAS CITY · 2022 · $387,500

## Abstract

Project Summary
Metabotropic glutamate (mGlu) receptor 2 is a presynaptic receptor enriched in active zones of
glutamatergic nerve terminals within the striatum and is pivotal for brain functions and some
mental illnesses. Recently, we found that Ca2+/calmodulin-dependent protein kinase II (CaMKII)
directly binds to mGlu2 receptors and phosphorylates mGlu2 receptors at a threonine residue in
the intracellular C-terminal tail. These findings for the first time reveal the mGlu2 receptor as a
direct substrate of CaMKII. Encouraged by this novel discovery, we propose this renewal
application to systematically study this previously unrecognized CaMKII-mGlu2 coupling and to
explore roles of CaMKII and mGlu2 receptors in the pathogenesis and symptomatology of a
common mental illness. Our hypothesis is that CaMKII regulates mGlu2 receptors and links
mGlu2 plasticity to depression-like behavior. Using multidisciplinary approaches, this hypothesis
will be tested both in vitro and in vivo in the following four inter-supportive Aims. Aim I will
characterize fundamental protein biochemistry of the CaMKII-mGlu2 interplay in vitro. Aim II will
define the regulation of CaMKII-mGlu2 interactions and mGlu2 receptor phosphorylation by
changing Ca2+ signals in striatal glutamatergic nerve terminals in vivo. Aim III will explore
functional roles of CaMKII in modulating trafficking and subcellular expression of mGlu2 receptors
and in controlling the efficacy of various mGlu2 signaling events. Aim IV will first monitor long-
lasting neuroadaptations of the striatal CaMKII-mGlu2 system in response to prolonged social
isolation in adult rats, a chronic stress paradigm modeling anhedonic depression in adulthood
animals. Aim IV will then clarify functional roles of CaMKII-mGlu2 interactions in the isolation-
induced depression-like behavior. Results achieved here will conceptually advance our current
understanding of a phosphorylation-dependent mechanism in regulating glutamate receptor
signaling at presynaptic sites. They will also ultimately contribute to the development of novel
pharmacotherapies, by targeting CaMKII and mGlu2 receptors, for the treatment of core
symptoms of depression.

## Key facts

- **NIH application ID:** 10385765
- **Project number:** 5R01MH061469-22
- **Recipient organization:** UNIVERSITY OF MISSOURI KANSAS CITY
- **Principal Investigator:** QIANG WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2000-12-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385765

## Citation

> US National Institutes of Health, RePORTER application 10385765, Molecular Regulation of Metabotropic Glutamate Receptors in Striatal Neurons (5R01MH061469-22). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10385765. Licensed CC0.

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