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

Canals, Meritxell; Poole, Daniel P.; Veldhuis, Nicholas A.; Schmidt, Brian L.; Bunnett, Nigel W.


Daniel P. Poole

Nicholas A. Veldhuis

Brian L. Schmidt

Nigel W. Bunnett


G protein-coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. Within 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 amongst cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of over one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have revealed 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 revealed 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.


Canals, M., Poole, D. P., Veldhuis, N. A., Schmidt, B. L., & Bunnett, N. W. (2019). G protein-coupled receptors are dynamic regulators of digestion and targets for digestive diseases. Gastroenterology, 156(6), 1600-1616.

Journal Article Type Article
Acceptance Date Jan 7, 2019
Online Publication Date Feb 13, 2019
Publication Date 2019-05
Deposit Date Jan 11, 2019
Publicly Available Date Feb 14, 2020
Journal Gastroenterology
Electronic ISSN 1528-0012
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 156
Issue 6
Pages 1600-1616
Keywords Abbreviations: AKAPs, A-kinase anchoring proteins; ARRB, beta-arrestin; ARRB2, beta-arrestin2; CGRP, calcitonin gene-related peptide; CLR, calcitonin receptor-like receptor; DOR, delta opioid receptor; DREADDs, Designer Receptors Exclusively Activated by
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Additional Information This article is maintained by: Elsevier; Article Title: G-Protein–Coupled Receptors Are Dynamic Regulators of Digestion and Targets for Digestive Diseases; Journal Title: Gastroenterology; CrossRef DOI link to publisher maintained version:; Content Type: article; Copyright: © 2019 by the AGA Institute


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