Evidence map›Paper›PMID 39919161›Full record

ArticleMolecular pharmacology2025

Role of the G protein-coupled receptor kinase 2/3 N terminus in discriminating the endocytic effects of opioid agonist drugs.

Joy Li, Asuka Inoue, Aashish Manglik, Mark von Zastrow

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. G-protein regulatory network governs receptor internalization dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  2. Review
  3. Article
  4. Opioid receptors reveal a discrete cellular mechanism of endosomal G protein activation.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  5. Article
  6. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors.

Joy LiTetrad Graduate Program, Department of Biochemistry and Biophysics, University of California San Francisco School of Medicine, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, California, USA; Quantitative Biology Institute, University of California San Francisco, San Francisco, California, USA.
Asuka InoueGraduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan; Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto, Japan.
Aashish ManglikQuantitative Biology Institute, University of California San Francisco, San Francisco, California, USA; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA; Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA.
Mark von ZastrowDepartment of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, California, USA; Quantitative Biology Institute, University of California San Francisco, San Francisco, California, USA. Electronic address: mark@vzlab.org.

Funding

PROTEINS REGULATING ENDOCYTOSIS OF OPIOID RECEPTORSR01DA012864 · NIDA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Mark E Von Zastrow · 2000 to 2026
$7.9M
Membrane Trafficking of Opioid and Adrenergic ReceptorsR01DA010711 · NIDA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI VONZASTROW, MARK E · 2014 to 2023
$4.6M
GPR88 localization to primary cilia and its impact on striatal cAMP signalingR01MH120212 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI VONZASTROW, MARK E · 2019 to 2023
$2.0M
NIDA NIH HHS R01 DA010711NIDA NIH HHS R01 DA012864NIH HHS R01MH120212NIMH NIH HHS R01 MH120212
6 · The paper itself

Abstract

Endocytosis of the μ-type opioid receptor (MOR) is a fundamentally important cellular regulatory process that is characteristically driven less effectively by partial relative to full agonist ligands. Such agonist-selective endocytic discrimination depends on how strongly drugs promote MOR binding to β-arrestins, and this, in turn, depends on how strongly they stimulate phosphorylation of the MOR cytoplasmic tail by G protein-coupled receptor kinases (GRKs) from the GRK2/3 subfamily. While these relatively "downstream" steps in the agonist selective endocytic pathway are now well defined, it remains unclear how agonist-bound receptors are distinguished "upstream" by GRKs. Focusing on GRK2 as a prototype, we show that this single GRK subtype can distinguish the endocytic activities of different MOR agonists in cells lacking other GRKs and that agonist selectivity is introduced at the most upstream step of GRK2 binding to MOR. This interaction requires prior membrane recruitment of GRK2 by its conserved Pleckstrin homology domain and is enhanced by phosphorylation of the MOR tail, but neither reaction can explain the high degree of agonist selectivity in the observed interaction of GRK2 with MOR. We identify the N-terminal domain (NTD) of GRK2, which is identical in GRK3, as a discrete element required for the full agonist selectivity of MOR-GRK2 interaction and show that the NTD is also required for GRK2 to promote MOR endocytosis after it is bound. We propose a simple cellular mechanism of upstream agonist discrimination that is organized as a series of biochemical checkpoints and uses the NTD as an agonist-selective sensor. SIGNIFICANCE STATEMENT: This study investigates how G protein-coupled receptor kinases (GRKs) distinguish the effects of opioid agonist drugs on regulated endocytosis of the μ-type opioid receptor (MOR). It shows that a single GRK subtype is sufficient to determine the agonist selectivity of MOR internalization, agonists are distinguished by how strongly they promote GRK2 recruitment by MOR, and the GRK2/3 N terminus is a key determinant of agonist discrimination.

Indexed as

Analgesics, OpioidEndocytosisG-Protein-Coupled Receptor Kinase 2G-Protein-Coupled Receptor Kinase 3Receptors, Opioid, muAnimalsHEK293 CellsHumansMicePhosphorylationAnalgesics, OpioidG-Protein-Coupled Receptor Kinase 2G-Protein-Coupled Receptor Kinase 3GRK2 protein, humanReceptors, Opioid, muArrestinEndocytosisFunctional selectivityGPCRGRKOpioid

Identifiers

PMID39919161
PMCPMC13095455

What OpenQuestion holds

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LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.