Allosterism within δ Opioid–κ Opioid Receptor Heteromers in Peripheral Sensory Neurons: Regulation of κ Opioid Agonist Efficacy

Jacobs, Blaine A.; Pando, Miryam M.; Jennings, Elaine M.; Chavera, Teresa A.; Clarke, William P.; Berg, Kelly A.

doi:10.1124/mol.117.109975

Cited by 19 publications

(26 citation statements)

References 37 publications

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“…The main strategies to target GPCR heteromers are the generation of selective compounds, which exhibit higher efficacy in tissues from wild type animals or in cells expressing both receptors than in knock-out animals tissues or in cell only expressing the individual receptors (Akgün et al, 2013; Gomes et al, 2013a; Molero et al, 2015; Nimczick and Decker, 2015; Peterson et al, 2017). Likewise, the use of membrane-permeable peptides that target the dimerization interface or heteromer-selective antibodies that can recognize an epitope in the heteromer but not in the individual protomers, have been most useful to detect GPCRs heteromers in vivo (Gupta et al, 2010; He et al, 2011; Viñals et al, 2015; Gomes et al, 2016a; Moreno et al, 2017; Jacobs et al, 2018). Finally, it is important to note the existence of single-molecule techniques, which are ideal for understanding the conformational complexity and dynamic signaling of GPCRs (Tian et al, 2017).…”

Section: The Discovery Of the Cannabinoid Receptorsmentioning

confidence: 99%

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

et al. 2019

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The endocannabinoid system (ECS) has been placed in the anti-cancer spotlight in the last decade. The immense data load published on its dual role in both tumorigenesis and inhibition of tumor growth and metastatic spread has transformed the cannabinoid receptors CB1 (CB1R) and CB2 (CB2R), and other members of the endocannabinoid-like system, into attractive new targets for the treatment of various cancer subtypes. Although the clinical use of cannabinoids has been extensively documented in the palliative setting, clinical trials on their application as anti-cancer drugs are still ongoing. As drug repurposing is significantly faster and more economical than de novo introduction of a new drug into the clinic, there is hope that the existing pharmacokinetic and safety data on the ECS ligands will contribute to their successful translation into oncological healthcare. CB1R and CB2R are members of a large family of membrane proteins called G protein-coupled receptors (GPCR). GPCRs can form homodimers, heterodimers and higher order oligomers with other GPCRs or non-GPCRs. Currently, several CB1R and CB2R-containing heteromers have been reported and, in cancer cells, CB2R form heteromers with the G protein-coupled chemokine receptor CXCR4, the G protein-coupled receptor 55 (GPR55) and the tyrosine kinase receptor (TKR) human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2). These protein complexes possess unique pharmacological and signaling properties, and their modulation might affect the antitumoral activity of the ECS. This review will explore the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it, and will develop on the value of cannabinoid receptor heteromers as potential new targets for anti-cancer therapies and as prognostic biomarkers.

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Section: The Discovery Of the Cannabinoid Receptorsmentioning

confidence: 99%

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

et al. 2019

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“…Associations entre récepteurs opioïdes : vers de Les hétéromères mu-kappa ont été uniquement décrit dans la moelle épinière chez la ratte en période de pré-oestrus où leur co-activation par la dynorphine et la morphine entraîne une augmentation de l'analgésie spinale induite par la morphine [2]. La présence d'hétéromères delta-kappa a quant à elle été établie dans les neurones sensoriels primaires de rats [3,4] où leur ciblage sélectif produit une analgésie thermique durable résultant de leur interaction fonctionnelle [4,5].…”

Section: Section Jeunes Chercheuses Et Jeunes Chercheursunclassified

Associations entre récepteurs opioïdes : vers de nouvelles stratégies thérapeutiques pour la douleur et l’addiction

Gaborit

Massotte

2019

Douleur analg

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Les récepteurs opioïdes modulent de nombreuses fonctions physiologiques. Ces récepteurs peuvent s’associer entre eux pour former une nouvelle entité fonctionnelle nommée hétéromère dotée de propriétés fonctionnelles spécifiques. Des études in vivo ont révélé que ces hétéromères jouaient un rôle crucial dans la douleur aiguë et chronique ainsi que dans l’addiction, les désignant alors comme une nouvelle cible thérapeutique pour le traitement de ces pathologies.

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“…Although there is abundant evidence for formation of GPCR heteromers in heterologous expression systems, there is comparatively little evidence for a functional role for heteromers in physiologically relevant systems. We recently published compelling evidence for the presence of functional DOP-KOP heteromers in adult rat peripheral sensory neurons in culture and in vivo (Berg et al, 2012;Jacobs et al, 2018). In cultured sensory neurons, DOP and KOP coimmunoprecipitate and a DOP-KOP heteromer-selective antibody augments the antinociceptive efficacy of the DOP agonist 5]-enkephalin (DPDPE) in vivo (Berg et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Further, ligands for DOP allosterically regulate KOP antinociceptive signaling and vice versa. These allosteric effects are abolished by transmembrane peptides or siRNA-induced knockdown or DOP or KOP individually both in cultured neurons as well as in vivo (Jacobs et al, 2018). Interestingly, due to allosteric effects, one ligand, 6'-guanidinonaltrindole (6'-GNTI), is a selective agonist at the DOP-KOP heteromer in adult rat peripheral sensory neurons.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, due to allosteric effects, one ligand, 6'-guanidinonaltrindole (6'-GNTI), is a selective agonist at the DOP-KOP heteromer in adult rat peripheral sensory neurons. 6'-GNTI binds to both DOP and KOP individually without efficacy in rat peripheral sensory neurons, but by binding to DOP in the DOP-KOP heteromer, 6'-GNTI allosterically enhances its own efficacy at KOP, both ex vivo and in vivo (Jacobs et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Signaling characteristics and functional regulation of delta opioid-kappa opioid receptor (DOP-KOP) heteromers in peripheral sensory neurons

et al. 2019

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Receptor heteromers often display distinct pharmacological and functional properties compared to the individual receptor constituents. In this study, we compared the properties of the DOP-KOP heteromer agonist, 6'-guanidinonaltrindole (6'-GNTI), with agonists for DOP ([D-Pen2,5]enkephalin [DPDPE]) and KOP (U50488) in peripheral sensory neurons in culture and in vivo. In primary cultures, all three agonists inhibited PGE 2 -stimulated cAMP accumulation as well as activated extracellular signal-regulated kinase ½ (ERK) with similar efficacy. ERK activation by U50488 was Gi-protein mediated but that by DPDPE or 6'-GNTI was Gi-protein independent (i.e., pertussis toxin insensitive). Brief pretreatment with DPDPE or U50488 resulted in loss of cAMP signaling, however, no desensitization occurred with 6'-GNTI pretreatment. In vivo, following intraplantar injection, all three agonists reduced thermal nociception. The dose-response curves for DPDPE and 6'-GNTI were monotonic whereas the curve for U50488 was an inverted U-shape. Inhibition of ERK blocked the downward phase and shifted the curve for U50488 to the right. Following intraplantar injection of carrageenan, antinociceptive responses to either DPDPE or U50488 were transient but could be prolonged with inhibitors of 12/15-lipoxgenases (LOX). By contrast, responsiveness to 6'-GNTI remained for a prolonged time in the absence of LOX inhibitors. Further, pretreatment with the 12/15-LOX metabolites, 12-and 15hydroxyeicosatetraenoic acid, abolished responses to U50488 and DPDPE but had no effect on 6'-GNTI-mediated responses either in cultures or in vivo. Overall, these results suggest that DOP-KOP heteromers exhibit unique signaling and functional regulation in peripheral sensory neurons and may be a promising therapeutic target for the treatment of pain.

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Allosterism within δ Opioid–κ Opioid Receptor Heteromers in Peripheral Sensory Neurons: Regulation of κ Opioid Agonist Efficacy

Cited by 19 publications

References 37 publications

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

Associations entre récepteurs opioïdes : vers de nouvelles stratégies thérapeutiques pour la douleur et l’addiction

Signaling characteristics and functional regulation of delta opioid-kappa opioid receptor (DOP-KOP) heteromers in peripheral sensory neurons

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