# Entropic Redistribution Drives the GRK-Independent Binding of Arrestin 2 to the Cannabinoid 2 Receptor

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2024 · $48,974

## Abstract

Contact PD/PI: Shriver, Thomas J.
PROJECT SUMMARY
Arrestins are an important class of secondary messenger proteins involved in signal transduction at G protein-
coupled receptors (GPCRs) throughout the human body. They underpin cascades associated with nociception,
planning, mood regulation, anxiety, and depression – all higher order functions misregulated in individuals with
addiction disorders. Despite arrestins’ involvement in many clinically important processes, our understanding of
their function on a molecular basis still lags behind the “canonical” secondary messengers at GPCRs, G
proteins. This is due in large part to the complicated regulation and activity of arrestins, which were initially
thought to simply downregulate GPCR signaling through endocytosis. A far more sophisticated view has
evolved in recent years, showing that an interplay between extracellular ligand, receptor, local membrane
environment, and intracellular kinases (GRKs) all play a role in directing arrestin recruitment. Due to the
multicomponent nature of these interactions and their inherently dynamic nature, structural studies revealing
the detailed molecular workings of arrestin signaling regulation have been cumbersome. Recent advances in
nuclear magnetic resonance (NMR) have enabled high resolution structures of some GPCR/arrestin
complexes, but a significant barrier remaining is recapitulating the complex regulation of arrestin recruitment
via GRKs. The spatial and temporal resolution of GRK phosphorylation allows these receptors to fine tune their
selection of arrestin signaling pathway but also creates an incredibly complicated landscape for structural
biologists. This difficulty is lessened if GRKs are not always required for arrestin recruitment, an idea that is
finding traction within the GPCR community. Recent studies have shown that the cannabinoid 2 receptor
(CB2R) can recruit arrestins in GRK knock-down cell lines and that this recruitment is sensitive to mutations in
acidic glutamate and aspartate residues within the receptor C-terminus. Removal of the putative requirement of
GRKs will facilitate NMR techniques uniquely capable of delineating the individual molecular components and
dynamics of the interactions between GPCRs and arrestins. Such techniques will require advanced statistical
treatment which is accessible to me through multiple Northwestern classes. My project seeks to show that
CB2R is a suitable target for this simplification strategy and that this methodology is translational in nature,
allowing similar approaches at other GPCR targets. I hypothesize that there exists a spectrum of GRK
dependence for arrestin recruitment across GPCR phylogeny, enabling a reduction in system complexity for
biochemical study through appropriate receptor selection. An understanding of such interactions may
eventually allow the development of novel pharmaceuticals designed using dynamics-informed structural
approaches.

## Key facts

- **NIH application ID:** 10898228
- **Project number:** 1F31DA060484-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Thomas Shriver
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898228

## Citation

> US National Institutes of Health, RePORTER application 10898228, Entropic Redistribution Drives the GRK-Independent Binding of Arrestin 2 to the Cannabinoid 2 Receptor (1F31DA060484-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10898228. Licensed CC0.

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