# Mechanisms Regulating Endocytosis of Opioid Receptors

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $355,393

## Abstract

PROJECT SUMMARY
This proposal seeks to elucidate how G protein-coupled receptors (GPCRs) are regulated by naturally
produced ligands and addictive drugs, focusing at the cell biological level as the critical bridge linking molecular
and systems-level events and understanding. GPCRs represent the largest family of signaling receptors,
comprise in aggregate the largest class of therapeutic drug targets, and mediate directly or indirectly the
effects of all addictive drugs. Accordingly, while addictive drug action in the CNS is our particular focus, the
proposed studies have broad potential application across GPCR family members and pathophysiological
processes. Our over-arching goal is to develop a fundamental understanding of GPCR regulation, discovering
the underlying cell biology and then elucidating its molecular basis, and through this path discover new targets
and strategies for potential therapeutic manipulation of addictive and other complex brain disorders that are
characterized by underlying disturbances of GPCR signaling or GPCR-dependent physiological regulation.
Progress in the previous funding period focused on defining sites of regulatory phosphorylation in the mu
opioid receptor, accomplishing this in intact human cells expressing the full spectrum of endogenous kinases at
native levels. We defined two critical regions of phosphorylation and carried out detailed cell biological
analysis of one of them, both in a heterologous cell model and a physiologically relevant population of CNS-
derived neurons. During the course of these studies we made some major unanticipated progress, including
development of conformational biosensor technology, discovery of GPCR signaling via heterotrimeric G
proteins from endosomes, and discovery of an unprecedented behavior of arrestin proteins suggesting a new
cellular operating mode of arrestins, downstream of and after dissociating from an activating GPCR. The
proposed studies seek to develop and extend these fundamental new observations and develop them to the
point of rational consideration as new molecular targets and cell-based strategies for therapeutics.

## Key facts

- **NIH application ID:** 9936389
- **Project number:** 5R01DA012864-20
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Mark E VonZastrow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,393
- **Award type:** 5
- **Project period:** 2000-09-28 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936389

## Citation

> US National Institutes of Health, RePORTER application 9936389, Mechanisms Regulating Endocytosis of Opioid Receptors (5R01DA012864-20). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9936389. Licensed CC0.

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