# Mechanisms and Cellular Function of Opioid Receptor Endocytosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $377,238

## Abstract

Abstract
Opioid and catecholamine receptors are key regulators of neurophysiology and behavior, and are important
targets of therapeutic and abused drugs. These receptors all belong to the G protein-coupled receptor (GPCR)
superfamily, the largest group of signaling receptors expressed in animals and a very important class of drug
targets. GPCRs signal by allostery and are extensively regulated after ligand-induced activation by
phosphorylation, endocytosis and interacting with a class of cytoplasmic adaptor proteins called arrestins.
These regulatory processes are critically important to the actions of addictive drugs, which are typically
administered repeatedly or over a prolonged period, and there is evidence for considerable diversity of the
effects of drugs on these processes. The present research program is focused on elucidating the fundamental
mechanistic basis of such selective regulation. In the previous funding period, we delineated drug-selective
biochemical modes by which a functionally relevant GPCR kinase is recruited from the cytoplasm by opioid
receptors. We also identified evidence for a discrete form of biased drug action determined by differences in
the subcellular location of receptor activation. We also discovered a distinct mechanism of cellular arrestin
regulation that defined by being independent of receptor phosphorylation. The proposed studies seek to extend
this fundamental research effort with the goal of developing new understanding that can be leveraged for
therapeutic benefit. Specifically, we propose to (1) Define an allosteric basis for agonist-selective
phosphorylation of opioid receptors; (2) Delineate localization and trafficking of opioid-relevant adenylyl cyclase
isoforms; and (3) Determine if β-arrestin has a phosphorylation-independent role in opioid drug discrimination.

## Key facts

- **NIH application ID:** 10366098
- **Project number:** 2R01DA012864-21
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Mark E VonZastrow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $377,238
- **Award type:** 2
- **Project period:** 2000-09-28 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366098

## Citation

> US National Institutes of Health, RePORTER application 10366098, Mechanisms and Cellular Function of Opioid Receptor Endocytosis (2R01DA012864-21). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10366098. Licensed CC0.

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