Comprehensive 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

被引:4
作者
Mansour, Ahmed [1 ,2 ]
Nagi, Karim [3 ]
Dallaire, Paul [1 ,2 ]
Lukasheva, Viktoriya [4 ]
Le Gouill, Christian [4 ]
Bouvier, Michel [4 ]
Pineyro, Graciela [1 ,2 ]
机构
[1] Univ Montreal, Fac Med, Dept Pharmacol & Physiol, Montreal, PQ H3T 1J4, Canada
[2] CHU St Justine Res Ctr, Montreal, PQ H3T 1C5, Canada
[3] Qatar Univ, Coll Med, QU Hlth, Doha, Qatar
[4] Univ Montreal, Inst Res Immunol & Canc, Dept Biochem & Mol Med, Montreal, PQ H3T 1J4, Canada
基金
加拿大健康研究院; 加拿大自然科学与工程研究理事会;
关键词
G-BETA-GAMMA; ADENYLYL-CYCLASE; BIASED AGONISM; RAT MODEL; TOLERANCE; MORPHINE; ACTIVATION; KINASE; PHOSPHORYLATION; INTERNALIZATION;
D O I
10.1021/acsptsci.1c00019
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Prolonged 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 delta-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 E-max and Log(tau) values for the different responses. The classification process revealed that the similarity in G alpha/G beta gamma, but not in beta-arrestin (beta arr), responses was correlated with the potential of Met-ENK, deltorphin IL (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 Gai/o activation, availability of G beta gamma subunits 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 G alpha i/o subunits but was independent of the G beta gamma dimer and Ca2+ mobilization, relying instead on Src and Raf-1 to induce this cellular adaptation.
引用
收藏
页码:1483 / 1498
页数:16
相关论文
共 89 条
  • [1] Abdallah K, 2018, HANDB EXP PHARMACOL, V247, P147, DOI 10.1007/164_2017_32
  • [2] Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis
    Atwood B.K.
    Lopez J.
    Wager-Miller J.
    Mackie K.
    Straiker A.
    [J]. BMC Genomics, 12 (1)
  • [3] Internalization and Src activity regulate the time course of ERK activation by delta opioid receptor ligands
    Audet, N
    Paquin-Gobeil, M
    Landry-Paquet, O
    Schiller, PW
    Piñeyro, G
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (09) : 7808 - 7816
  • [4] Differential Association of Receptor-Gβγ Complexes with β-Arrestin2 Determines Recycling Bias and Potential for Tolerance of Delta Opioid Receptor Agonists
    Audet, Nicolas
    Charfi, Iness
    Mnie-Filali, Ouissame
    Amraei, Mohammad
    Chabot-Dore, Anne-Julie
    Millecamps, Magali
    Stone, Laura S.
    Pineyro, Graciela
    [J]. JOURNAL OF NEUROSCIENCE, 2012, 32 (14) : 4827 - 4840
  • [5] Chronic opioid treatment induces adenylyl cyclase V superactivation - Involvement of G beta gamma
    AvidorReiss, T
    Nevo, I
    Levy, R
    Pfeuffer, T
    Vogel, Z
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (35) : 21309 - 21315
  • [6] Protein kinase C and epidermal growth factor stimulation of Raf1 potentiates adenylyl cyclase type 6 activation in intact cells
    Beazely, MA
    Alan, JK
    Watts, VJ
    [J]. MOLECULAR PHARMACOLOGY, 2005, 67 (01) : 250 - 259
  • [7] Regulatory properties of adenylate cyclases type 5 and 6: A progress report
    Beazely, MA
    Watts, VJ
    [J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 2006, 535 (1-3) : 1 - 12
  • [8] Exploring use of unsupervised clustering to associate signaling profiles of GPCR ligands to clinical response
    Benredjem, Besma
    Gallion, Jonathan
    Pelletier, Dennis
    Dallaire, Paul
    Charbonneau, Johanie
    Cawkill, Darren
    Nagi, Karim
    Gosink, Mark
    Lukasheva, Viktoryia
    Jenkinson, Stephen
    Ren, Yong
    Somps, Christopher
    Murat, Brigitte
    Van Der Westhuizen, Emma
    Le Gouill, Christian
    Lichtarge, Olivier
    Schmidt, Anne
    Bouvier, Michel
    Pineyro, Graciela
    [J]. NATURE COMMUNICATIONS, 2019, 10 (1)
  • [9] AN OPERATIONAL MODEL OF PHARMACOLOGICAL AGONISM - THE EFFECT OF E/[A] CURVE SHAPE ON AGONIST DISSOCIATION-CONSTANT ESTIMATION
    BLACK, JW
    LEFF, P
    SHANKLEY, NP
    WOOD, J
    [J]. BRITISH JOURNAL OF PHARMACOLOGY, 1985, 84 (02) : 561 - 571
  • [10] Contribution of Adenylyl Cyclase Modulation of Pre- and Postsynaptic GABA Neurotransmission to Morphine Antinociception and Tolerance
    Bobeck, Erin N.
    Chen, QiLiang
    Morgan, Michael M.
    Ingram, Susan L.
    [J]. NEUROPSYCHOPHARMACOLOGY, 2014, 39 (09) : 2142 - 2152