Molecular basis of proton sensing by G protein-coupled receptors
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Abstract
Three proton-sensing G protein-coupled receptors (GPCRs)-GPR4, GPR65, and GPR68-respond to extracellular pH to regulate diverse physiology. How protons activate these receptors is poorly understood. We determined cryogenic-electron microscopy (cryo-EM) structures of each receptor to understand the spatial arrangement of proton-sensing residues. Using deep mutational scanning (DMS), we determined the functional importance of every residue in GPR68 activation by generating ∼9,500 mutants and measuring their effects on signaling and surface expression. Constant-pH molecular dynamics simulations provided insights into the conformational landscape and protonation patterns of key residues. This unbiased approach revealed that, unlike other proton-sensitive channels and receptors, no single site is critical for proton recognition. Instead, a network of titratable residues extends from the extracellular surface to the transmembrane region, converging on canonical motifs to activate proton-sensing GPCRs. Our approach integrating structure, simulations, and unbiased functional interrogation provides a framework for understanding GPCR signaling complexity.
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Self-citationGαs‐coupled GPCR s GPR 65 and GPR 174. Downers for immune responses
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Elucidating the Activation Mechanism of the Proton-sensing GPR68 Receptor
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Popp, N. A., Powell, R. L., Wheelock, M. K., Holmes, K. J., Zapp, B. D., Sheldon, K. M., Fletcher, S. N., Wu, X., Fayer, S., Rubin, A. F., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.01.587474 · Cited by 6 · see citing works
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Accurate variant effect estimation in FACS-based deep mutational scanning data with Lilace
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MPBuild: An Automated Pipeline for High-Fidelity Membrane Protein Simulation System Construction
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GPR68, A Proton-sensing GPCR, Mediates Acid-induced Visceral Nociception
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Implementation and Validation of Titratable Cysteine in GROMACS-Based Constant-pH Molecular Dynamics
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Peptide ligand discovery of G protein-coupled receptors
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Tip funnel-shaped nanochannels sensor for high-flux chloride transport inspired by CLC
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Self-citationHuman GPR174 deficiency drives polyclonal lymphoproliferative disease via defects in T cell functionPreprint
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Application of nanoparticles for targeting G protein-coupled receptors
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The second extracellular loop gates Stachel-mediated activation of ADGRG6/GPR126Preprint
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- Authors
- Howard, M. K., Hoppe, N., Huang, X.-P., Mitrovic, D., Billesbølle, C. B., Macdonald, C. B., Mehrotra, E., Rockefeller Grimes, P., Trinidad, D. D., Delemotte, L., English, J. G., Coyote-Maestas, W., & Manglik, A.
- Affiliations
- University of California, San Francisco (US)
- University of North Carolina at Chapel Hill (US)
- Science for Life Laboratory (SE)
- University of Utah (US)
- Corresponding author
- Manglik, Aashish
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2025-02
- Volume
- 188
- Issue
- 3
- Pages
- 671-687.e20
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC11849372
- OpenAlex
- W4405989080
- Cited by
- 77
- References
- 108
- Citations by year
- 2026: 36 · 2025: 36 · 2024: 5
- FWCI
- 21.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Vetenskapsrådet (VR 2019 - 02433)
- National Institute of General Medical Sciences (T32GM141323, 5T32GM139786, 1F32GM152977)
- National Institutes of Health (S10OD021741, U24 GM129541)
- Howard Hughes Medical Institute
- The Chan Zuckerberg Initiative
- Edward Mallinckrodt Jr Foundation
- Goran Gustafsson's Foundations
- National Cancer Institute
- Center for High Performance Computing
- Knut och Alice Wallenbergs Stiftelse
- Vallee Foundation
- National Institute of Allergy and Infectious Diseases (1F31AI157438)
- National Heart Lung and Blood Institute (F31HL164045)
- University of California, San Francisco
- Göran Gustafssons Stiftelse för Naturvetenskaplig och Medicinsk Forskning
- National Institute of Mental Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- proton-sensing GPCRs, GPR4, GPR65, GPR68, extracellular pH, titratable residues, deep mutational scanning, cryo-EM structure, constant pH molecular dynamics, GPCR activation, conformational landscape
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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