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Cited by 35Receptor Mechanisms and SignalingGastrointestinal motility and disordersNeuropeptides and Animal Physiology

G-protein–coupled receptors are dynamic regulators of digestion and targets for digestive diseases

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Canals, Meritxell, Poole, Daniel P., Veldhuis, Nicholas A., Schmidt, Brian L., Bunnett, Nigel W.·2019·Gastroenterology
DOI 10.1053/j.gastro.2019.01.266PMC PMC6508858
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Abstract

G-protein-coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. In the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication among cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of more than one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have shown that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs and has shown opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract.

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  • Confounders in terms of prevalent POTS co-morbidities (such as IBS or depression) were not controlled for in the study of serum activity against GPCRs.

    “Confounders in terms of prevalent POTS co-morbidities (such as IBS or depression) which may have elicited their own bi-directional effects on immune responses (Canals et al., 2019”

    From Self-reported symptom burden in postural orthostatic tachycardia syndrome (POTS): A narrative review of observational and interventional studies (2023) · cites this paper as Canals et al., 2019

    The sections on GPCR oligomers and allosteric modulators discuss IBS treatments, but do not address POTS, serum activity against GPCRs, or whether a study controlled for comorbidities. Searches for POTS, serum autoantibodies, depression, and bidirectional immune responses found no passage supporting the attributed claim. Page numbers were unavailable in our copy. (LLM, conf=0.76)

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Cited by

Sorted by citations

Authors
Canals, M., Poole, D. P., Veldhuis, N. A., Schmidt, B. L., & Bunnett, N. W.
Affiliations
  • University of Nottingham (GB)
  • Australian Research Council (AU)
  • New York University (US)
Corresponding author
Bunnett, Nigel W.
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2019-05
Volume
156
Issue
6
Pages
1600-1616
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2019.01.266
PMC
PMC6508858
OpenAlex
W2913426593
Cited by
35
References
10
Citations by year
2026: 6 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 7 · 2021: 4 · 2020: 5 · 2019: 1 · 2018: 1
FWCI
0.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
Funders
  • National Institutes of Health (NS102722, DK118971, DE026806)
  • U.S. Department of Defense (W81XWH1810431)
  • National Health and Medical Research Council (1121029)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
G protein-coupled receptors, digestion, gastrointestinal diseases, gastrointestinal tract, allosteric modulation, biased agonism, receptor oligomerization, compartmentalized signaling, drug discovery, gastrointestinal epithelial cells
MeSH terms
Allosteric Regulation, Digestion, Digestive System Diseases, Humans, Endosomes, Signal Transduction, Dimerization, Receptors, G-Protein-Coupled, Drug Discovery

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