Agonist-Specific Regulation of μ-Opioid Receptor Desensitization and Recovery from Desensitization

Virk, Michael S.; Williams, John T.

doi:10.1124/mol.107.042952

Cited by 48 publications

(52 citation statements)

References 32 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7A and Table 1). This observation is consistent with prior reports of DAMGOinduced receptor desensitization (Celver et al, 2001;Virk and Williams, 2008) and with images shown in Fig. 3B of DAMGO-induced receptor internalization.…”

Section: Mor-tyr166 Phosphorylation Reduces Agonist Efficacy 341supporting

confidence: 82%

Phosphorylation of the μ-Opioid Receptor at Tyrosine 166 (Tyr3.51) in the DRY Motif Reduces Agonist Efficacy

et al. 2009

View full text Add to dashboard Cite

The effects of phosphorylation of the tyrosine residue in the highly conserved DRY motif expressed in the putative second cytoplasmic loop of the -opioid receptor were assessed after expression in human embryonic kidney (HEK) 293 cells. Tyrosine kinase activation by epidermal growth factor (EGF) or hydrogen peroxide treatment effectively increased phosphorylation of the tyrosine-166 in the -opioid receptor (MORTyr166p) as measured by a novel phosphoselective antibody. We were surprised to find that the increase in MOR-Tyr166p immunoreactivity (ir) required coactivation by the opioid agonist [D-Ala 2 ,methyl-Phe 4 ,Gly 5 -ol]enkephalin (DAMGO), as demonstrated by both Western blot imaging of membrane proteins and confocal microscopy of transfected cells; MOR-Tyr166p-ir did not significantly increase after either DAMGO, EGF, or H 2 O 2 treatment alone. The increase in MOR-Tyr166p-ir was blocked by pretreatment with the opioid antagonist naloxone or the Src kinase inhibitor 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidine. Consistent with these data, mutation of the tyrosine-166 to phenylalanine blocked the increased immunoreactivity, and untransfected HEK293 cells did not increase MOR-Tyr166p-ir after treatment. DAMGO The -opioid receptor (MOR; OPRM1) belongs to the class A (rhodopsin family) G i/o -coupled family of G-protein-coupled receptors (GPCRs) and functions to reduce neuronal excitability primarily by increasing potassium conductance and inhibiting voltage-gated calcium channels (Law et al., 2000;Williams et al., 2001). The opioid system is usually described within the context of drug abuse and analgesic drug action; however, the normal physiological role of the opioid system is to regulate pain sensitivity, endocrine functioning, gut motility, and smooth muscle tone in response to physiological stressors (López et al., 1999;Drolet et al., 2001). The regulation of -opioid signaling is a dynamic and complex process (Law et al., 2000). A primary desensitization mechanism involving G-protein receptor kinase (GRK) and ␤-arrestindependent internalization through cytoplasmic serine/threonine phosphorylation has been well described previously (Celver et al., 2001(Celver et al., , 2004Williams et al., 2001). In addition, MOR contains four highly conserved cytoplasmic tyrosine residues (Thompson et al., 1993), and tyrosine kinase-mediated mechanisms regulating MOR signaling have also been described previously (McLaughlin and Chavkin, 2001;Zhang et al., 2009). Tyrosine phosphorylation may influence MOR trafficking and signaling (Pak et al., 1999), consistent with the effects of tyrosine phosphorylation on internalization and signaling of the ␦-and -opioid receptors (Kramer et al., 2000;Appleyard et al., 2000). A recent study by Law and colleagues showed that tyrosine phosphorylation of MOR at Tyr166 and Tyr336 controlled the switch from inhibition to

show abstract

Section: Mor-tyr166 Phosphorylation Reduces Agonist Efficacy 341supporting

confidence: 82%

Phosphorylation of the μ-Opioid Receptor at Tyrosine 166 (Tyr3.51) in the DRY Motif Reduces Agonist Efficacy

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Previous studies (Yu et al, 1997;Virk and Williams, 2008) suggested that the ability of saturating concentrations of MOPr agonists to induce acute (0 -10-min) desensitization is agonist efficacy-dependent. On this basis, endomorphin-2 would be predicted to induce relatively little desensitization of MOPr-mediated GIRK activation during this relatively short period of agonist exposure, because of its lower efficacy for this effect.…”

Section: Discussionmentioning

confidence: 99%

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Rivero¹,

Llorente²,

McPherson³

et al. 2012

Mol Pharmacol

101

View full text Add to dashboard Cite

Previously we correlated the efficacy for G protein activation with that for arrestin recruitment for a number of agonists at the -opioid receptor (MOPr) stably expressed in HEK293 cells. We suggested that the endomorphins (endomorphin-1 and -2) might be biased toward arrestin recruitment. In the present study, we investigated this phenomenon in more detail for endomorphin-2, using endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in brainstem locus ceruleus slices, the peptide agonists [DAla 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO) and endomorphin-2 activated inwardly rectifying K ϩ current in a concentrationdependent manner. Analysis of these responses with the operational model of pharmacological agonism confirmed that endomorphin-2 had a much lower operational efficacy for G protein-mediated responses than did DAMGO at native MOPr in mature neurons. However, endomorphin-2 induced faster desensitization of the K ϩ current than did DAMGO. In addition, in HEK293 cells stably expressing MOPr, the ability of endomorphin-2 to induce phosphorylation of Ser375 in the COOH terminus of the receptor, to induce association of arrestin with the receptor, and to induce cell surface loss of receptors was much more efficient than would be predicted from its efficacy for G protein-mediated signaling. Together, these results indicate that endomorphin-2 is an arrestin-biased agonist at MOPr and the reason for this is likely to be the ability of endomorphin-2 to induce greater phosphorylation of MOPr than would be expected from its ability to activate MOPr and to induce activation of G proteins.

show abstract

“…Differences in agonist-mediated desensitization of OR responsiveness have also been observed in locus ceruleus brain slice preparations. In these neurons, methadone and DAMGO cause rapid desensitization of Met-enkephalin-induced Kir3 currents after short-term exposure (10 min) in whole-cell patch-clamp recordings, whereas morphine, morphine-6-glucuronide, and oxycodone lead to far less desensitization in these same preparations (Alvarez et al, 2002;Virk and Williams, 2008). Moreover, in locus ceruleus neurons from transgenic mice expressing an epitope-tagged FLAG-OR, Met-enkephalin, etorphine, methadone, morphine, and oxymorphone all induce significant desensitization of Met-enkephalin-induced hyperpolarizations, whereas oxycodone does not (Arttamangkul et al, 2008).…”

Section: Biased Agonism With Respect To Receptor Desensitizationmentioning

confidence: 99%

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

et al. 2011

View full text Add to dashboard Cite

Agonist-Specific Regulation of μ-Opioid Receptor Desensitization and Recovery from Desensitization

Cited by 48 publications

References 32 publications

Phosphorylation of the μ-Opioid Receptor at Tyrosine 166 (Tyr3.51) in the DRY Motif Reduces Agonist Efficacy

Phosphorylation of the μ-Opioid Receptor at Tyrosine 166 (Tyr3.51) in the DRY Motif Reduces Agonist Efficacy

Endomorphin-2: A Biased Agonist at the μ-Opioid Receptor

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

Contact Info

Product

Resources

About