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.

Highlights

  • ENDOGENOUS BIASED AGONISM The last decade has witnessed the experimental confirmation of previous theoretical concepts demonstrating that GPCRs exist in many temporally related micro-conformations (Deupi and Kobilka, 2010)

  • Different ligands binding to the same receptor stabilize distinct receptor conformations linked to different signaling pathways and physiological outcomes

  • This paradigm whereby different ligands, binding to the same GPCR in an identical cellular background, promote distinct receptor conformational states linked to a different functional outcome has been termed biased agonism or functional selectivity

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Summary

Introduction

ENDOGENOUS BIASED AGONISM The last decade has witnessed the experimental confirmation of previous theoretical concepts demonstrating that GPCRs exist in many temporally related micro-conformations (Deupi and Kobilka, 2010). There are several functionally important GPCR families that bind to multiple endogenous agonists [for example chemokine, somatostatin (SST), and opioid receptors (ORs)]. In this focused review we provide an overview of the existing literature regarding two of these GPCR families with multiple endogenous peptide ligands, opioids and SST, in the context of the gastrointestinal tract (GIT).

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