Kinetic model of partial agonism reveals cellular basis of ligand efficacy.

Michael Ritt, Nishaben Patel, Edgardo Sánchez Rivas, Sivaraj Sivaramakrishnan

Abstract read

In one paragraph

Article in The Journal of biological chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it

0cells of the map it votes in

0citing papers in PubMed

–field-weighted citation impact

1 · What the graph read from it

What it found

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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

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3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

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5 · Who and what money

Authors and funding

4 authors.

Michael RittDepartment of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.

Nishaben PatelDepartment of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.

Edgardo Sánchez RivasBiochemistry, Molecular Biology and Biophysics Graduate Program, University of Minnesota, Minneapolis, Minnesota, USA.

Sivaraj SivaramakrishnanDepartment of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA; Biochemistry, Molecular Biology and Biophysics Graduate Program, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address: sivaraj@umn.edu.

Funding

Emergent cellular functions of GPCRs and myosinsR35GM126940 · NIGMS · UNIVERSITY OF MINNESOTA · PI Sivaraj Sivaramakrishnan · 2018 to 2026

$3.8M

NIGMS NIH HHS R35 GM126940

6 · The paper itself

Abstract

Titrating G protein-coupled receptor (GPCR) signaling to achieve desired physiological outcomes without overdose can be accomplished through partial agonism rather than drug dosage. In this study, we use FRET-based biosensors in combination with ordinary differential equation modelling to identify two key kinetic features that determine agonist efficacy: the concentration-dependent association rate of the G protein to the agonist-bound receptor, and the catalytic rate of G protein activation by the receptor. While both rate constants scale proportionally with reported molecular efficacy metrics, we find that the concentration-dependent association rate is the governing parameter across multiple distinct GPCR-ligand pairings. Our model explains discrepancies in signaling outcomes observed between physiological observations and cellular model systems that rely on receptor overexpression.

Indexed as

Models, BiologicalReceptors, G-Protein-CoupledAnimalsFluorescence Resonance Energy TransferGTP-Binding ProteinsHumansKineticsLigandsSignal TransductionGTP-Binding ProteinsLigandsReceptors, G-Protein-Coupledcomputer modelingG proteinG protein-coupled receptor (GPCR)kineticsMichaelis-Mentenmolecular pharmacology

Identifiers

PMID42173251

DOI10.1016/j.jbc.2026.113180

PMCPMC13284481

What OpenQuestion holds

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LicenceCC BY

Read underepoch 390

Registered trials

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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.