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المؤلفMansour, Ahmed
المؤلفNagi, Karim
المؤلفDallaire, Paul
المؤلفLukasheva, Viktoriya
المؤلفLe Gouill, Christian
المؤلفBouvier, Michel
المؤلفPineyro, Graciela
تاريخ الإتاحة2022-02-13T09:23:26Z
تاريخ النشر2021-10-08
اسم المنشورACS Pharmacology and Translational Science
المعرّفhttp://dx.doi.org/10.1021/acsptsci.1c00019
الاقتباسG.P. was supported in part by the Canadian Institutes of Health Research (CIHR) grants Nos. MOP 324876 and MOP 79432 and the Natural Sciences and Engineering Research Council of Canada (NSERC) (311997). M.B. was supported by CIHR Foundation grant No. FDN 148431.
معرّف المصادر الموحدhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85115804501&origin=inward
معرّف المصادر الموحدhttp://hdl.handle.net/10576/26754
الملخصProlonged exposure to opioid receptor agonists triggers adaptations in the adenylyl cyclase (AC) pathway that lead to enhanced production of cyclic adenosine monophosphate (cAMP) upon withdrawal. This cellular phenomenon contributes to withdrawal symptoms, hyperalgesia and analgesic tolerance that interfere with clinical management of chronic pain syndromes. Since δ-opioid receptors (DOPrs) are a promising target for chronic pain management, we were interested in finding out if cell-based signaling profiles as generated for drug discovery purposes could inform us of the ligand potential to induce sensitization of the cyclase path. For this purpose, signaling of DOPr agonists was monitored at multiple effectors. The resulting signaling profiles revealed marked functional selectivity, particularly for Met-enkephalin (Met-ENK) whose signaling bias profile differed from those of synthetic ligands like SNC-80 and ARM390. Signaling diversity among ligands was systematized by clustering agonists according to similarities in Emax and Log(τ) values for the different responses. The classification process revealed that the similarity in Gα/Gβγ, but not in β-arrestin (βarr), responses was correlated with the potential of Met-ENK, deltorphin II, (d-penicillamine2,5)-enkephalin (DPDPE), ARM390, and SNC-80 to enhance cAMP production, all of which required Ca2+ mobilization to produce this response. Moreover, superactivation by Met-ENK, which was the most-effective Ca2+ mobilizing agonist, required Gαi/o activation, availability of Gβγsubunits at the membrane, and activation of Ca2+ effectors such as calmodulin and protein kinase C (PKC). In contrast, superactivation by (N-(l-tyrosyl)-(3S)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-l-phenylalanyl-l-phenylalanine (TIPP), which was set in a distinct category through clustering, required activation of Gαi/o subunits but was independent of the Gβγdimer and Ca2+ mobilization, relying instead on Src and Raf-1 to induce this cellular adaptation.
اللغةen
الناشرAmerican Chemical Society
الموضوعOpioid Receptors
morphine
Enkephalins
العنوانComprehensive Signaling Profiles Reveal Unsuspected Functional Selectivity of δ-Opioid Receptor Agonists and Allow the Identification of Ligands with the Greatest Potential for Inducing Cyclase Superactivation
النوعArticle
الصفحات1483-1498
رقم العدد5
رقم المجلد4
dc.accessType Open Access


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