# Structure and function of GPCR heteromeric complexes in brain

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $471,550

## Abstract

Major depressive disorder is a mental illness afflicting approximately 16% of the world population. Currently
available interventions including monoamine-based pharmacotherapies require several weeks to months for
beneficial effects to occur. In addition, these treatments are often accompanied by undesirable side effects.
Therefore, there is an urgent need for better antidepressant medications, with a faster onset of action, which will
also be effective in patients who do not respond to classical antidepressants. Recent clinical findings suggest
that psilocybin – a hallucinogenic serotonin 5-HT2A receptor (5-HT2AR) agonist, exerts fast-acting and long-lasting
antidepressant actions in patients suffering from major depression. Despite these striking effects, a number of
alterations in various mental domains, including sensory perception and thought processes, precludes the
routine use of psilocybin and other hallucinogens in daily clinical practice. G protein-coupled receptors (GPCRs)
are critical mediators of cell signaling. Although recognized as capable of activating G proteins in a monomeric
form, numerous studies reveal their possible association into hetero-oligomers, enabling allosteric crosstalk
between receptor protomers. We previously reported that 5-HT2AR and metabotropic glutamate receptor 2
(mGluR2) are able to interact physically to form a GPCR complex. Results from earlier versions of this R01 grant
showed that at least part of the cellular signaling and psychosis-like behaviors induced by hallucinogenic 5-
HT2AR agonists require expression of the 5-HT2AR-mGluR2 heteromer in the mouse frontal cortex. However, the
ability of cortical 5-HT2AR-mGluR2 to affect behavioral states associated with depression upon hallucinogen
administration remains to be elucidated. Similarly, as the functional importance of GPCR oligomerization remains
controversial, additional studies related to basic structural and signaling properties of the 5-HT2AR-mGluR2
complex are needed. Our published data and the preliminary data presented here support our working
hypothesis that inter-family GPCR heteromerization affects structure, sub-cellular localization and function of
both 5-HT2AR and mGluR2 in living mammalian cells. Our data are also consonant with the hypothesis that a
single dose of hallucinogenic 5-HT2AR agonists induces fast-acting and long-lasting effects on remission of
behavioral states associated with depression, and that these therapeutic-related phenotypes require expression
of 5-HT2AR and mGluR2 as a GPCR heteromer in the frontal cortex of mice. These data set the stage for a
uniquely comprehensive analysis of the molecular mechanism underlying the antidepressant effects of
hallucinogens, with the ultimate goal of developing safer, more effective, and non-hallucinogenic depression
treatment strategies.

## Key facts

- **NIH application ID:** 10003396
- **Project number:** 5R01MH084894-11
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Javier Gonzalez-Maeso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $471,550
- **Award type:** 5
- **Project period:** 2009-07-20 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003396

## Citation

> US National Institutes of Health, RePORTER application 10003396, Structure and function of GPCR heteromeric complexes in brain (5R01MH084894-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10003396. Licensed CC0.

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