# Chemical biology tools for investigating heteromeric complexes of cannabinoid receptors

> **NIH NIH K99** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $98,967

## Abstract

Project Summary
The Gi/o coupled cannabinoid receptors 1 and 2 (CB1 and CB2) co-express in central and peripheral tissues.
They individually play fundamental roles in membrane plasticity, vesicle secretion, cell migration, and
inflammation. While CB1 and CB2 receptors share only 40% structural homology, both are fully activated by 2-
arachidonoylglycerol (2-AG) and associate with the same G-proteins. Surprisingly, opposite signaling
outcomes have been reported after selective activation of CB1 or CB2 in both central and peripheral organs.
The two receptors are individually known to interact with several protein complexes beyond the established
role of heterotrimeric G-proteins, namely through heteromeric complexes with other G protein-coupled
receptors or receptor tyrosine kinases. Co-expressed CB1 and CB2 receptors are suggested to be juxtaposed
in a way that one's activation regulates the other's activity. As 2-AG activates both receptors, I hypothesize that
the endocannabinoid coordinates heteromerization mechanisms of CB1 and CB2 with other proteins. This
project aims at combining protein engineering and proteomics to investigate the prevalence, the biological
functions and the composition of cannabinoid receptor heteromers in living cells. CB1, CB2 and their
respective interactomes need to be jointly investigated to distinguish individual from synergistic effects on
cellular activity. Investigating the biological function of CB1 and CB2 heteromers in living cells ultimately
requires novel tools to activate, label and purify cannabinoid receptors and their interacting proteins.
Additionally, a new strategy to manipulate the formation of these protein complexes in a spatially and
temporally resolved manner is needed. The speed and complexity of heteromerization mechanisms are
challenging to capture with traditional techniques. I will develop new molecular tools for the study of
cannabinoid receptor heteromers including imaging tools and those to characterize and manipulate the CB1
and CB2 interactomes at the molecular level. The techniques involved in this project include cannabinoid
receptor visualization and photo-crosslinking, reversible manipulation of 2-AG levels, and manipulation of
heteromer formation by light. This K99/R00 award will broaden my education through critical training in
proteomics and cutting-edge protein engineering techniques.
Aim 1. To investigate subcellular locations and composition of heteromeric complexes of cannabinoid
receptors.
Aim 2. To investigate the biological function of endogenous receptor heteromer formation by light.

## Key facts

- **NIH application ID:** 10190434
- **Project number:** 1K99GM141316-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Aurelien Laguerre
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $98,967
- **Award type:** 1
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10190434

## Citation

> US National Institutes of Health, RePORTER application 10190434, Chemical biology tools for investigating heteromeric complexes of cannabinoid receptors (1K99GM141316-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10190434. Licensed CC0.

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