Agonist-biased Trafficking of Somatostatin Receptor 2A in Enteric Neurons

Zhao, Peishen; Canals, Meritxell; Murphy, Jane E.; Klingler, Diana; Eriksson, Emily M.; Pelayo, Juan–Carlos; Hardt, Markus; Bunnett, Nigel W.; Poole, Daniel P.

doi:10.1074/jbc.m113.496414

Cited by 37 publications

(36 citation statements)

References 32 publications

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“…SP stimulated interactions between the NK 1 R and ECE-1c and ECE-1d, which constitutively internalize in the same endosomes as GPCRs (22). ECE-1 similarly interacts with somatostatin 2A receptors (15). Whether such interactions enhance neuropeptide degradation remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Products were digested with BamHI and XhoI and ligated into pcDNA3-RLuc8 using the BamHI and XhoI sites. The bioluminescence resonance energy transfer (BRET) sensors (human) NK 1 R-RLuc8, ␤ARR1-YFP, ␤ARR2-YFP, ECE1a-d-YFP, KRas-Venus, Rab5a-Venus, and Rab11-Venus were generated as described previously (9,14,15). The FRET sensors CytoEKAR and NucEKAR (16) were from Addgene (Cambridge, MA) (plasmids 18680 and 18681, respectively).…”

Section: Methodsmentioning

confidence: 99%

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Endothelin-converting Enzyme 1 and β-Arrestins Exert Spatiotemporal Control of Substance P-induced Inflammatory Signals

Jensen¹,

Halls²,

Murphy

et al. 2014

Journal of Biological Chemistry

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Background: Agonists stimulate the subcellular redistribution of receptors. The importance of trafficking for pathophysiological processes is unknown. Results: Substance P inflammatory signaling required receptor interaction with ␤-arrestins and endothelin-converting enzyme, which mediated endocytosis and recycling. Conclusion: Sustained substance P inflammatory signaling requires receptor recycling. Significance: Mechanisms that maintain receptors at the cell surface are necessary for sustained signaling by extracellular agonists.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Endothelin-converting Enzyme 1 and β-Arrestins Exert Spatiotemporal Control of Substance P-induced Inflammatory Signals

Jensen¹,

Halls²,

Murphy

et al. 2014

Journal of Biological Chemistry

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“…Although not specifically examined, it is possible that the differences in MOR recycling may be related to susceptibility to degradation by endosomal peptidases, as demonstrated for ECE-2 (21). Previous studies have demonstrated that ECE-1 is a major determinant of receptor recycling and signaling in myenteric neurons (44,71). The retention of MOR following treatment with the nonpeptide MOR agonist loperamide, which is unlikely to be endopeptidase substrate, suggests that other mechanisms are likely to be involved.…”

Section: G260mentioning

confidence: 99%

“…Receptor endocytosis can also influence the type and duration of subsequent cellular signaling in response to MOR agonists (23). We examined ligand-induced MOR endocytosis and recycling in myenteric neurons using organotypic wholemount preparations as described previously (44,48,71). Under basal conditions, MOR-IR was localized to the cell surface of the soma and neurites of untreated neurons, with a lower proportion of total surface MOR-IR relative to other GPCRs examined in enteric neurons (NK 1 R, DOR, or SSTR 2A :…”

Section: Mor Is Expressed By Enteric Neurons Throughout the Gastrointmentioning

confidence: 99%

“…MOR trafficking in myenteric neurons using MOR-selective agents further Receptor trafficking assays. Agonist-induced MOR endocytosis was examined using organotypic preparations of the ileum as described in detail (44,48,71). Preparations were harvested in the presence of nicardipine and tetrodotoxin (100 nM, Alomone) and were recovered in Krebs buffer to allow complete MOR recycling (1 h, 37°C).…”

Section: Animalsmentioning

confidence: 99%

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

Lay

Carbone

DiCello

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Lay J, Carbone SE, DiCello JJ, Bunnett NW, Canals M, Poole DP. Distribution and trafficking of the -opioid receptor in enteric neurons of the guinea pig. Am J Physiol Gastrointest Liver Physiol 311: G252-G266, 2016. First published June 30, 2016 doi:10.1152/ajpgi.00184.2016.-The -opioid receptor (MOR) is a major regulator of gastrointestinal motility and secretion and mediates opiate-induced bowel dysfunction. Although MOR is of physiological and therapeutic importance to gut function, the cellular and subcellular distribution and regulation of MOR within the enteric nervous system are largely undefined. Herein, we defined the neurochemical coding of MOR-expressing neurons in the guinea pig gut and examined the effects of opioids on MOR trafficking and regulation. MOR expression was restricted to subsets of enteric neurons. In the stomach MOR was mainly localized to nitrergic neurons (ϳ88%), with some overlap with neuropeptide Y (NPY) and no expression by cholinergic neurons. These neurons are likely to have inhibitory motor and secretomotor functions. MOR was restricted to noncholinergic secretomotor neurons (VIP-positive) of the ileum and distal colon submucosal plexus. MOR was mainly detected in nitrergic neurons of the colon (nitric oxide synthase positive, 87%), with some overlap with choline acetyltransferase (ChAT) OPIATES HAVE BEEN USED FOR millennia for their analgesic properties and continue to be routinely used for the treatment of moderate to severe pain. Although opiate analgesics are effective, their use is associated with opioid-induced bowel dysfunction (OBD), a collection of on-target side effects that grossly impact gastrointestinal tract function. OBD can severely limit the use of opiates to treat pain, reducing patient quality of life and compliance, with intractable constipation the most significant problem (28).The direct inhibitory actions of opiates on the isolated colon were first demonstrated nearly a century ago by Trendelenburg. 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). Opiates, including morphine, mediate their effects on the gut through activation of the MOR expressed by enteric neurons, as demonstrated by mechanistic studies using selective MOR-targeting drugs and oprm1 Ϫ/Ϫ mice (reviewed by Refs. 52,70). In addition, peripherally restricted MOR antagonists, such as methylnaltrexone, have proven clinically efficacious in treating opiate-induced constipation. MOR agonists, including the peripherally restricted agonist loperamide, are commonly used as antidiarrheals.A large...

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Location bias: A “Hidden Variable” in GPCR pharmacology

Eiger,

Hicks,

Gardner

et al. 2023

BioEssays

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G protein‐coupled receptors (GPCRs) are the largest family of transmembrane receptors and primarily signal through two main effector proteins: G proteins and β‐arrestins. Many agonists of GPCRs promote “biased” responses, in which different cellular signaling pathways are activated with varying efficacies. The mechanisms underlying biased signaling have not been fully elucidated, with many potential “hidden variables” that regulate this behavior. One contributor is “location bias,” which refers to the generation of unique signaling cascades from a given GPCR depending upon the cellular location at which the receptor is signaling. Here, we review evidence that GPCRs are expressed at and traffic to various subcellular locations and discuss how location bias can impact the pharmacologic properties and characterization of GPCR agonists. We also evaluate how differences in subcellular environments can modulate GPCR signaling, highlight the physiological significance of subcellular GPCR signaling, and discuss the therapeutic potential of exploiting GPCR location bias.

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Agonist-biased Trafficking of Somatostatin Receptor 2A in Enteric Neurons

Cited by 37 publications

References 32 publications

Endothelin-converting Enzyme 1 and β-Arrestins Exert Spatiotemporal Control of Substance P-induced Inflammatory Signals

Endothelin-converting Enzyme 1 and β-Arrestins Exert Spatiotemporal Control of Substance P-induced Inflammatory Signals

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

Location bias: A “Hidden Variable” in GPCR pharmacology

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