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.

Keywords: Drug Discovery; G Proteins; Receptors; Signal Transduction; Trafficking.

Figure 1

GPCRs and their ligands in digestion and digestive disease. GPCRs are expressed throughout the digestive tract. Expression of some functionally and clinically important GPCRs in specific cell types in the tongue, lower esophageal sphincter, stomach, small intestine, and colon are depicted. GPCRs control multiple processes in the gut and are targets for common diseases (eg, GERD, gastric ulcer disease, disorders of intestinal motility, colonic pain, and inflammation). 5HT_xR, serotonin receptor; CLR, calcitonin receptor-like receptor; EP3, prostaglandin receptor 3; FFARs, free fatty acid receptors; GABA_BR, GABA B receptor; H_xR, histamine receptor; M_xR, muscarinic acetylcholine receptor; NKR, neurokinin receptor; OTR, oxytocin receptor; P2YR, purinergic 2Y receptor; RAMP1, receptor activity modifying protein 1; TGR5, Takeda GPCR 5 bile-acid receptor; T_xR, taste receptor; VPR, vasopressin receptor.

Figure 2

Allosteric modulation of GPCRs. The orthosteric site of a GPCR is the site where the endogenous ligand (brown) binds. Sites that are topographically distinct from the orthosteric site are known as allosteric sites. Ligands that bind to allosteric sites (red) can potentiate (PAMs) or depress (NAMs) orthosteric ligand affinity and efficacy. The simulated concentration response curves show the effect of increasing concentrations of PAMs (green lines) or NAMs (red lines) on the response to a GPCR agonist (black line).

Figure 3

The therapeutic potential of biased agonists of GPCRs. Biased agonism describes the phenomenon in which different ligands binding to the same GPCR in an identical cellular background elicit distinct signaling outcomes (path-ways A and B). Balanced agonists (ligand 1) are those that activate all signaling pathways to the same extent, leading to therapeutic effects but also to deleterious effects. When there is a distinction between the signaling pathways that drive a therapeutic response and those that mediate the adverse effects of a drug, biased agonists provide a novel avenue for pathway-directed therapeutics. In such a case, the drug would only trigger the desired response and spare the unwanted, deleterious effects (ligand 2).

Figure 4

Potential roles of GPCR dimerization. GPCRs have been shown to function as monomers (1) and dimers (2). (3) The formation of GPCR dimers can be triggered by agonist activation and change the specificity of G-protein coupling. (4) Such differences in effector coupling elicited by dimerization have prompted the development of bivalent drugs, which specifically target the 2 protomers within a dimer. (5) Dimerization also can provide an alternative mechanism of receptor trafficking, in which ligands can promote the co-internalization of the 2 receptors after the stimulation of only 1 protomer. Alternatively, the presence of a protomer that is resistant to agonist-promoted endocytosis, within a heterodimer, can inhibit the internalization of the complex.

Figure 5

GPCR trafficking and compartmentalized signaling. The formation of GPCR-mediated signaling platforms provides a mechanism to sculpt specific cellular responses. (1) GPCRs at the plasma membrane form multiprotein complexes that participate in the regulation of a specific signaling pathway (pathway A). For example, AKAP interactions with GPCRs can scaffold the formation of complexes that regulate cAMP signaling by bringing in close proximity enzymes that degrade cAMP (PDEs) and kinases that are activated by this second messenger (PKA). (2) With prolonged agonist stimulation, GPCRs are phosphorylated by GRKs. The phosphorylated receptor has higher affinity for the cytosolic protein ARRB. (3) ARRBs are adaptors that promote clathrin-and dynamin-mediated endocytosis of GPCRs. (4) ARRBs scaffold the formation of multi-protein complexes that result in a second wave of intracellular signaling (pathway B). Genetically encoded biosensors have shown differences in the spatial and temporal profile of GPCR signaling from different subcellular locations (insets). AKAP, A-kinase anchor protein; GRK, G-protein receptor kinase; PDE, phosphodiesterase; PKA, protein kinase A.