Surgical intervention has also been shown to increase dynorphin expression in the dorsal root ganglia of mice (Romero et al

Surgical intervention has also been shown to increase dynorphin expression in the dorsal root ganglia of mice (Romero et al., 2012), and stimulate release of opioid peptides from enteric neurons after abdominal medical procedures in guinea pigs (Patierno et al., 2005). mechanisms to finely tune physiological responses. We propose that further characterization of K-7174 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 K-7174 area of research and we will highlight the difficulties that need to be addressed when examining endogenous bias in tissues and in animals. Keywords:biased agonism, enteric nervous system, G protein-coupled receptor, somatostatin, somatostatin receptor, opioid, opioid receptor == ENDOGENOUS BIASED AGONISM == The last decade has witnessed the experimental confirmation of previous theoretical concepts demonstrating that K-7174 GPCRs exist in many temporally related micro-conformations (Deupi and Kobilka, 2010). Mechanistically, this inherent plasticity is in line with recent biophysical studies indicating that GPCRs can adopt multiple active states that can be differentially stabilized by chemically distinct classes of ligands (Hofmann et al., 2009;Bokoch et al., 2010). Such plasticity allows GPCRs to mediate a spectrum of acute signaling and longer-term regulatory behaviors that can be activated in a ligand-specific manner. Indeed, it is now established K-7174 that different agonists do not uniformly activate all cellular signaling pathways linked to a given receptor. Rather, different K-7174 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 says linked to a different functional outcome has been termedbiased agonismorfunctional selectivity. Therapeutically, biased agonism provides new avenues for the development of drugs that are not only receptor-specific but also pathway-specific. As such it has opened the field to the discovery of ligands that selectively activate signaling pathways mediating desired physiological effects whilst minimizing on-target side-effects that are elicited by activation of other signaling pathwaysviathe same receptor. To date, most descriptions of biased agonism have focused on the differential effects of synthetic drugs. However, there are several functionally important GPCR families that bind to multiple endogenous agonists [for example chemokine, somatostatin (SST), and opioid receptors (ORs)]. Although this has been traditionally attributed to the redundancy of some biological systems, biased agonism could represent an added layer of control to engender finely tuned physiological responses. Indeed, recent reports have already highlighted the potential for functional selectivity across the chemokine receptor family (Rajagopal et al., 2013;Zweemer et al., 2014). 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). The opioid system is usually a prototypical example of potential biological redundancy, and it also represents one of the first examples where functional selectivity of synthetic drugs has been reported in the context of gut physiology. On the other hand, SST receptors are therapeutic targets in treating GI disease (e.g., diarrhea, bleeding varices, neuroendocrine tumors) and SSTs and related peptides also represent BWS a well-characterized system where multiple endogenous ligands of the same receptor exist within the GIT (Zhao et al., 2013). Importantly, these two receptor systems also reveal different mechanisms that can explain distinct physiological outcomes derived from activation of the same receptor by different ligands. == THE SOMATOSTATIN SYSTEM OF THE GUT == There are five members of the SST receptor family (SSTR1-5) and their distribution in the GIT has been recently reviewed (Van Op den Bosch et al., 2009). Somatostatin, originally known as somatotropin release-inhibiting factor (SRIF), was first identified and characterized as a cyclic tetradecapeptide (Brazeau et al., 1973). It was predicted that SST-14 was a product of a larger peptide precursor and that other forms with potential biological activity were likely to exist. Indeed, it is now known that SST arises from maturation of preprosomatostatin (PPSST),.