G-Protein–Coupled Receptors Are Dynamic Regulators of Digestion and Targets for Digestive Diseases

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.

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon

“…One way through which GPCRs may functionally interact is through the sharing or recruitment of the same intracellular proteins. 16 Distinct GPCRs can also directly interact with other receptors to form a unique signaling unit known as a heteromer. The MOR and delta opioid receptor (DOR) heteromer (MOR-DOR) is a well-characterized example and has been identified as a potential target for pain therapy, 17 although this model has recently been challenged.…”

“…Such functional interaction may be detected as heterologous desensitization whereby activation of a protomer with a selective agonist desensitizes the response of the other protomer to its corresponding agonist. 16 This interaction was examined in the colon by first exposing preparations to an agonist for one receptor (1 mmol/L, 5 minutes) and then measuring subsequent responses to either the same agonist or to an agonist for the other receptor (homologous and heterologous desensitization, respectively).…”

“…GPCRs may interact at the cellular level through alternative mechanisms including heterologous desensitization. 16 Very few studies have specifically examined heterologous GPCR desensitization in the ENS. Activation of the neurokinin 1 receptor (NK 1 R) desensitized neurokinin 3 receptor (NK 3 R)- Figure 9D) and CYM51010.…”

Inflammation without pain: Immune‐derived opioids hold the key

“…28,29 PAMs of the mu and delta opioid receptor subtypes have been characterized. 28,29 PAMs of the mu and delta opioid receptor subtypes have been characterized.…”

“…Positive allosteric modulators (PAMs) bind to G protein-coupled receptors (GPCRs) at topographically distinct sites to orthosteric ligands, leading to potentiation of receptor signaling. 28,29 PAMs of the mu and delta opioid receptor subtypes have been characterized. 30 These provide a pharmacological mechanism through which endogenous signaling may be selectively enhanced when and where this occurs, thereby retaining the spatiotemporal dynamics required for normal physiological processes.…”