Biological redundancy of endogenous GPCR ligands in the gut and the potential for endogenous functional selectivity

Abstract

This review focuses on the existence and function of multiple endogenous agonists of the somatostatin and opioid receptors with an emphasis on their expression in the gastrointestinal tract. These agonists generally arise from the proteolytic cleavage of prepropeptides during peptide maturation or from degradation of peptides by extracellular or intracellular endopeptidases. In other examples, endogenous peptide agonists for the same G protein-coupled receptors can be products of distinct genes but contain high sequence homology. This apparent biological redundancy has recently been challenged by the realization that different ligands may engender distinct receptor conformations linked to different intracellular signaling profiles and, as such the existence of distinct ligands may underlie mechanisms to finely tune physiological responses. We propose that further characterization of signaling pathways activated by these endogenous ligands will provide invaluable insight into the mechanisms governing biased agonism. Moreover, these ligands may prove useful in the design of novel therapeutic tools to target distinct signaling pathways, thereby favoring desirable effects and limiting detrimental on-target effects. Finally we will discuss the limitations of this area of research and we will highlight the difficulties that need to be addressed when examining endogenous bias in tissues and in animals.

Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

“…Although this is poorly explored, these differences may reflect the relative prevalence of distinct G protein-mediated and noncanonical pathways that a receptor can couple to in different cell types. Importantly, such variation expands the diversity and utility of endogenous ligands and their receptors (Thompson et al, 2014) beyond the currently fashionable view of "biased" ligands that favor engagement with one signaling pathway over another in a single cell type (Violin et al, 2014;Luttrell et al, 2015). FFA4 is such a pleotropic GPCR (Milligan et al, 2015), able to generate a range of physiologic endpoints in different cell types by engaging distinct signaling pathways.…”

Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig

“…It is now established that opioids and opiates mediate their effects through actions at the ␦-, -, and -opioid G proteincoupled receptors (DOR, KOR, and MOR). These receptors are activated by over 20 endogenous opioid peptides that are generated by differential processing and cleavage of larger precursors, many of which are expressed within the gut (63). Endogenous opioid peptides, including endorphins, enkephalins, and dynorphins, are important regulators of gastrointestinal function and have dampening effects on motility and secretomotor function (70).…”

New directions for urotensin II receptor ligands

“…Because downstream signaling is tightly coupled to specific ligand/receptor interactions, structurally different ligands will therefore modulate differently downstream signaling events. While most descriptions of biased agonism have been centered on the differential effects of synthetic drugs, there are however several important GPCR families that bind to multiple endogenous agonists such as somatostatin and opioid receptors . Although this has been traditionally attributed to the redundancy of some biological systems, biased agonism/functional selectivity represents an added layer of control to engender finely tuned physiological responses.…”