μ-Opioid-Induced Desensitization of Opioid Receptor-Like 1 and μ-Opioid Receptors: Differential Intracellular Signaling Determines Receptor Sensitivity

Mandyam, Chitra D.; Thakker, Deepak R.; Standifer, Kelly M.

doi:10.1124/jpet.103.051599

Cited by 26 publications

(27 citation statements)

References 41 publications

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“…Moreover, PKC inhibitor and PKG inhibitor had no effects on isoproterenol-induced H1R phosphorylation, suggesting that neither PKC nor PKG is involved in heterologous H1R phosphorylation induced by b2R activation. Involvement of GRKs in heterologous receptor phosphorylation has been demonstrated (21). This report demonstrated that m -opioid receptor stimulation with its agonist led to translocate the GRKs to the membrane, and these kinases are involved in the other Fig.…”

Section: Discussionmentioning

confidence: 77%

β2-Adrenergic Receptor-Mediated Histamine H1 Receptor Down-Regulation: Another Possible Advantage of β2 Agonists in Asthmatic Therapy

et al. 2004

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Abstract. To clarify heterologous regulation of a receptor is important in considering medication. Histamine constricts the airway smooth muscle through the action to the H 1 receptor (H1R), which contributes to asthma. b 2 -Adrenergic receptor (b2R) agonists are widely used in asthmatic therapy for their bronchodilating effects. In this study, we investigated the effect of b2R activation on the H1R function using Chinese hamster ovary cells stably co-expressing human histamine H1R and b2R (CHO-H1/ b2 cell). The stimulation of b2R resulted in the decrease of H1R in the membrane. Heterologous H1R down-regulation was significantly reversed in the presence of the cyclic AMP-dependent protein kinase (PKA) inhibitor KT5720. Since phosphorylation of G protein-coupled receptor (GPCR) by second messenger-dependent kinases, is proposed to be a key step initiating heterologous receptor desensitization, we examined whether heterologous H1R down-regulation was accompanied by H1R phosphorylation. H1R was phosphorylated by b2R stimulation; however, a PKA inhibitor did not inhibit heterologous H1R phosphorylation. Our results suggest that H1R was heterologously regulated by b2R. Not only a direct action of b2R agonist to b2R causing bronchodilation but also indirect action that reduces the number of H1R responsible for bronchoconstriction might contribute to a decrease in the bronchial resistance, which proposes another possible advantage of b2R agonists for asthmatic medication.

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Section: Discussionmentioning

confidence: 77%

β2-Adrenergic Receptor-Mediated Histamine H1 Receptor Down-Regulation: Another Possible Advantage of β2 Agonists in Asthmatic Therapy

et al. 2004

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“…A 1 hour treatment of BE(2)-C human neuroblastoma cells with the mu agonist DAMGO reduced N/OFQ-mediated inhibition of cAMP accumulation. Although the same treatment of SH-SY5Y cells was ineffective in reducing N/OFQ signaling (Mandyam et al, 2000(Mandyam et al, , 2003. Likewise, in CHO or HEK 293 overexpressing recombinant NOP and mu receptors, mu receptor activation had no effect on NOP receptor-mediated stimulation of ERK1/2 (Hawes et al, 1998) or inhibition of cAMP .…”

Section: Cross Talk With Mu Opioid Receptorsmentioning

confidence: 94%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

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“…To test the roles of GRK2 and GRK3 in OFQ/N-induced receptor desensitization in Flag-BE cells, we used GRK isoform-specific antisense DNA treatment, which we reported previously selectively reduces levels of GRK2 or GRK3 Mandyam et al, 2003). OFQ/ N-induced receptor desensitization was attenuated in cells pretreated with GRK2 antisense but not GRK2 sense DNA (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…The role of GRK2 in OFQ/N-mediated increase in receptor phosphorylation in Flag-BE cells was tested by depleting GRK2 levels with GRK2 antisense DNA treatment, as described previously (Aiyar et al, 2000;Thakker and Standifer, 2002;Mandyam et al, 2003). This GRK2 antisense DNA treatment reduced GRK2 levels more than 50% (Fig.…”

Section: Resultsmentioning

confidence: 96%

“…OFQ/N binds to NOP receptors and activates protein kinase C, which plays a role in homologous NOP receptor desensitization (Lou et al, 1997;Pei et al, 1997;Pu et al, 1999;Mandyam et al, 2002). Besides homologous NOP receptor desensitization, activation of NOP receptors by OFQ/N heterologously regulates the receptor response to DAMGO (Hawes et al, 1998;Mandyam et al, 2000Mandyam et al, , 2003Thakker and Standifer, 2002).…”

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confidence: 99%

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Orphanin FQ/Nociceptin Potentiates [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin–Induced μ-Opioid Receptor Phosphorylation

Ozsoy¹,

Thakker²,

Standifer³

2005

Mol Pharmacol

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In this study, we investigate the molecular mechanisms by which acute orphanin FQ/nociceptin (OFQ/N), acting through the nociceptin opioid peptide (NOP) receptor, desensitizes the -opioid receptor. We described previously the involvement of protein kinase C and G-protein-coupled receptor kinases (GRK) 2 and 3 in OFQ/N-induced receptor desensitization. Because phosphorylation of the receptor triggers the successive regulatory mechanisms responsible for desensitization, such as receptor uncoupling, internalization, and down-regulation, we investigated the ability of OFQ/N to modulate [D-Ala 2 ,N-MePhe 4 ,Gly 5 -ol]-enkephalin (DAMGO)-induced receptor phosphorylation in BE(2)-C human neuroblastoma cells transfected with epitope-tagged receptors. OFQ/N treatment (100 nM, 60 min) potentiated DAMGO-induced receptor phosphorylation; inhibition of GRK2 or protein kinase C concomitant with OFQ/N treatment blocked the OFQ/N-mediated increase in DAMGOinduced phosphorylation. Inclusion of the NOP antagonist peptide III-BTD during OFQ/N pretreatment blocked the potentiation of DAMGO-induced phosphorylation by OFQ/N, which is consistent with the potentiation being mediated via actions of the NOP receptor. In addition, in cells expressing receptors in which the GRK-mediated phosphorylation site Ser 375 was mutated to alanine, OFQ/N treatment failed to potentiate DAMGOinduced receptor phosphorylation and failed to desensitize the receptor. However, DAMGO-induced receptor phosphorylation and OFQ/N-induced receptor desensitization occurred in cells expressing receptors lacking non-GRK phosphorylation sites. These data suggest that OFQ/N binds to NOP receptors and activates protein kinase C, which then increases the ability of GRK2 to phosphorylate the agonist-occupied receptor, heterologously regulating homologous receptor desensitization.Receptor agonists acting through -opioid receptors are widely used analgesics in the treatment of severe pain, despite the fact that long-term treatment with these drugs results in the development of tolerance and dependence. At the molecular level, receptor desensitization or loss of receptor function has been suggested to be the underlying reason for the development of tolerance to receptor agonists (Harrison et al., 1998).Like many GPCRs, the receptor can undergo homologous and heterologous receptor desensitization. Homologous receptor desensitization occurs when a cognate agonist leads to a decrease in the receptor responsiveness through the induction of regulatory events such as phosphorylation, internalization, and down-regulation of the receptor, and it often involves G-protein-coupled receptor kinases (GRKs). Agonist binding to receptor stimulates G proteins, and the ␤␥ subunits of activated G proteins recruit GRKs to the plasma membrane, in which GRKs can phosphorylate agonistoccupied receptors (Lefkowitz et al., 1998). Several GRK2-mediated phosphorylation sites of the receptor have been identified, but Ser 375 seems to be the primary site for DAMGO-induced receptor phosphoryla...

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μ-Opioid-Induced Desensitization of Opioid Receptor-Like 1 and μ-Opioid Receptors: Differential Intracellular Signaling Determines Receptor Sensitivity

Cited by 26 publications

References 41 publications

β2-Adrenergic Receptor-Mediated Histamine H1 Receptor Down-Regulation: Another Possible Advantage of β2 Agonists in Asthmatic Therapy

β2-Adrenergic Receptor-Mediated Histamine H1 Receptor Down-Regulation: Another Possible Advantage of β2 Agonists in Asthmatic Therapy

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Orphanin FQ/Nociceptin Potentiates [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin–Induced μ-Opioid Receptor Phosphorylation

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μ-Opioid-Induced Desensitization of Opioid Receptor-Like 1 and μ-Opioid Receptors: Differential Intracellular Signaling Determines Receptor Sensitivity

Cited by 26 publications

References 41 publications

β2-Adrenergic Receptor-Mediated Histamine H1 Receptor Down-Regulation: Another Possible Advantage of β2 Agonists in Asthmatic Therapy

β2-Adrenergic Receptor-Mediated Histamine H1 Receptor Down-Regulation: Another Possible Advantage of β2 Agonists in Asthmatic Therapy

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Orphanin FQ/Nociceptin Potentiates [D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin–Induced μ-Opioid Receptor Phosphorylation

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Orphanin FQ/Nociceptin Potentiates [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin–Induced μ-Opioid Receptor Phosphorylation