Opioid Receptor Function Is Regulated by Post-endocytic Peptide Processing

Gupta, Achla; Gomes, Ivone; Wardman, Jonathan H.; Devi, Lakshmi A.

doi:10.1074/jbc.m113.537704

Cited by 19 publications

(19 citation statements)

References 68 publications

(110 reference statements)

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“…This target is unlikely to mediate the antiangiogenic activity of quininib because alternative endothelin receptor antagonists do not phenocopy quininib (data not shown). In addition, recently Gupta et al (50) reported that the quininib Z-isomer more potently inhibits ECE-2 than the E-isomer, which does not correlate with our finding of greater anti- angiogenic activity of the E-isomer (50). Also of note is that quininib does not directly inhibit the activity of any VEGF receptor.…”

Section: Discussioncontrasting

confidence: 49%

Phenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis

Reynolds

Álvarez

Sasore

et al. 2016

Journal of Biological Chemistry

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Retinal angiogenesis is tightly regulated to meet oxygenation and nutritional requirements. In diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, uncontrolled angiogenesis can lead to blindness. Our goal is to better understand the molecular processes controlling retinal angiogenesis and discover novel drugs that inhibit retinal neovascularization. Phenotype-based chemical screens were performed using the ChemBridge Diverset

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Section: Discussioncontrasting

confidence: 49%

Phenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis

Reynolds

Álvarez

Sasore

et al. 2016

Journal of Biological Chemistry

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“…Furthermore, Dyngo-4a pretreated cells also show cAMP inhibition suggesting that opto-MOR continues to inhibit cAMP from the plasma membrane with no loss of signal when inhibiting dynamin-clathrin pathways (Figure S3C and S3F). These data together suggest that opto-MOR may indeed recycle and use clathrin-dynamin endocytosis which has been documented in opioid receptors (Gupta et al, 2014) and other GPCR systems (Irannejad et al, 2013; Tsvetanova and von Zastrow, 2014), and suggests that opto-MOR may have some utility in dissecting these diverse signaling dynamics.…”

Section: Resultsmentioning

confidence: 53%

Spatiotemporal Control of Opioid Signaling and Behavior

Siuda

Copits

Schmidt

et al. 2015

Neuron

127

117

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Summary Optogenetics is now a widely accepted tool for spatiotemporal manipulation of neuronal activity. However, a majority of optogenetic approaches use binary on/off control schemes. Here we extend the optogenetic toolset by developing a neuromodulatory approach using a rationale-based design to generate a Gi-coupled, optically-sensitive, mu-opioid-like receptor, we term opto-MOR. We demonstrate that opto-MOR engages canonical mu-opioid signaling through inhibition of adenylyl cyclase, activation of MAPK and G protein-gated inward rectifying potassium (GIRK) channels, and internalizes with similar kinetics as the mu-opioid receptor. To assess in vivo utility we expressed a Cre-dependent viral opto-MOR in RMTg/VTA GABAergic neurons, which led to a real-time place preference. In contrast, expression of opto-MOR in GABAergic neurons of the ventral pallidum hedonic cold spot, led to real-time place aversion. This tool has generalizable application for spatiotemporal control of opioid signaling and, furthermore, can be used broadly for mimicking endogenous neuronal inhibition pathways.

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“…Receptor internalization assays were carried out using previously described protocols (52, 53). Briefly, HEK-293 cells expressing HA-tagged mGPR83 were seeded 24 hours after transfection into 24-well plates (2 × 10 5 cells per well).…”

Section: Methodsmentioning

confidence: 99%

Identification of GPR83 as the receptor for the neuroendocrine peptide PEN

et al. 2016

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PEN is an abundant peptide in the brain that has been implicated in the regulation of feeding. We identified a receptor for PEN in mouse hypothalamus and Neuro2A cells. PEN bound to and activated GPR83, a G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor (GPCR). Reduction of GPR83 expression in mouse brain and Neuro2A cells reduced PEN binding and signaling, consistent with GPR83 functioning as the major receptor for PEN. In some brain regions, GPR83 colocalized with GPR171, a GPCR that binds the neuropeptide bigLEN, another neuropeptide that is involved in feeding and is generated from the same precursor protein as is PEN. Coexpression of these two receptors in cell lines altered the signaling properties of each receptor, suggesting a functional interaction. Our data established PEN as a neuropeptide that binds GPR83 and suggested that these two ligand-receptor systems—PEN-GPR83 and bigLEN-GPR171—may be functionally coupled in the regulation of feeding.

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Opioid Receptor Function Is Regulated by Post-endocytic Peptide Processing

Cited by 19 publications

References 68 publications

Phenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis

Phenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis

Spatiotemporal Control of Opioid Signaling and Behavior

Identification of GPR83 as the receptor for the neuroendocrine peptide PEN

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