# Regulation of G protein-coupled receptor signaling and trafficking

> **NIH NIH R35** · THOMAS JEFFERSON UNIVERSITY · 2020 · $507,000

## Abstract

G protein-coupled receptors (GPCRs) play an essential role in coordinating the ability of cells to rapidly
respond to their environment. Agonist binding to a GPCR promotes initial activation of heterotrimeric G
proteins, which mediates downstream signaling. Agonist-occupied GPCRs then interact with GPCR kinases
(GRKs), which specifically phosphorylate the receptor, and arrestins, which bind to GRK-phosphorylated
receptors and function in GPCR desensitization, endocytosis, and signaling. A central question that drives
current GPCR research involves understanding the dynamics and structures of GPCR interactions with G
proteins, GRKs and arrestins. My laboratory is currently using a variety of strategies including X-ray
crystallography, biochemical and biophysical analysis, and molecular and cellular biology to better understand
the dynamics of GPCR regulation by GRKs and arrestins and the potential role of these processes in disease.
In this application, we propose to address four questions that are central to understanding the mechanisms
involved in GRK and arrestin regulation of GPCR signaling and trafficking. Can we obtain structural and
dynamic insight on a GPCR/GRK complex? While we currently know little about the critical regions that
mediate GRK interaction with GPCRs or how this interaction ultimately regulates GRK activation, our
preliminary studies reveal three binding “hot spots” between the β2-adrenergic receptor (β2AR) and GRK5 and
suggest large conformational changes in GRK5 upon binding to the receptor. How does β-arrestin interact with
the β2-adrenergic receptor and β2-adaptin? β-arrestins play a central role in regulating GPCR signaling and
trafficking so further understanding these interactions has important implications. Moreover, structural
differences in the receptor when bound to its major downstream targets should provide insight on candidate
regions to target in order to selectively enhance or disrupt specific interactions. Do α-arrestins play a broad
role in regulating GPCR trafficking and signaling? We have found that the α-arrestin ARRDC3 functions as a
switch to modulate the endosomal residence time and subsequent intracellular signaling of the β2AR. We will
perform structure/function analysis of ARRDC3 interaction with the β2AR and assess whether ARRDCs have a
broad role in regulating GPCR function. What is the molecular and structural basis of biased agonism? While it
is evident that biased signaling through a number of GPCRs may ultimately prove to be of significant
therapeutic value, literally nothing is known about the structural and mechanistic basis by which ligands can
bias GPCR signaling. Overall, a more detailed understanding into these questions has tremendous
implications for the development of more effective drugs to treat a wide variety of diseases.

## Key facts

- **NIH application ID:** 9978885
- **Project number:** 5R35GM122541-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Jeffrey L Benovic
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $507,000
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978885

## Citation

> US National Institutes of Health, RePORTER application 9978885, Regulation of G protein-coupled receptor signaling and trafficking (5R35GM122541-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9978885. Licensed CC0.

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