# Molecular mechanism of ABHD6 enzymatic activity in neurons

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2020 · $427,625

## Abstract

Summary
The most abundant endocannabinoids (eCB) in brain, 2-arachidonoyl glycerol (2-AG), is inactivated by two
distinct enzymes: monoacylglycerol lipase (MAGL) and hydrolase domain-contain 6 (ABHD6). The selective
inhibition of these enzymes increases the net levels of 2-AG in different neuronal compartments, presynaptic
and postsynaptic, respectively. Accordingly, selective inhibition of these enzymes induces different
spatiotemporal enhancement of 2-AG signaling and distinct or synergistic therapeutic benefits.
 We recently gathered results showing that ABHD6 hydrolyzes additional monoacylglycerol substrates than 2-
AG and that ABHD6 inhibitors increase the net levels of 2-AG only in highly activity neurons, suggesting a novel
molecular mechanism. To increase our mechanistic understanding of ABHD6 at the structural and atomic levels,
we initiated an effort and have now successfully purified several functional ABHD6 protein constructs ready for
structural analysis. Based on this premise, we propose the following two aims that will determine the:
Aim 1: Molecular mechanisms of ABHD6 enzymatic activity.
Aim 2: Structure function relationship of ABHD6.
Completion of the work outline in this new R21 grant proposal will provide a comprehensive understanding of
the role of ABHD6 in controlling eCB signaling in brain within the context of neurological diseases. Our long-term
goal is to increase our understanding of the role played by ABHD6 in healthy and diseased brain and help
develop novel therapeutics that lack the potential for abuse and adverse effects produced by classic cannabinoid
agonists.

## Key facts

- **NIH application ID:** 10040363
- **Project number:** 1R21NS118130-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Nephi Stella
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,625
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10040363

## Citation

> US National Institutes of Health, RePORTER application 10040363, Molecular mechanism of ABHD6 enzymatic activity in neurons (1R21NS118130-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10040363. Licensed CC0.

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