The Absence of a Direct Correlation between the Loss of [d-Ala2,MePhe4,Gly5-ol]Enkephalin Inhibition of Adenylyl Cyclase Activity and Agonist-induced μ-Opioid Receptor Phosphorylation

Kouhen, Rachid El; Kouhen, Odile Maestri El; Law, Ping Yee; Loh, Horace H.

doi:10.1074/jbc.274.14.9207

Cited by 55 publications

(55 citation statements)

References 34 publications

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“…By measuring the Gβγ-mediated [Ca 2+ ] i release, we demonstrate a rapid loss of OPRM1 responsiveness within minutes after morphine or DAMGO treatment. Furthermore, this time course of receptor desensitization correlated to the rate of receptor phosphorylation and βArrs recruitment that were reported previously [8,17].…”

Section: Discussionsupporting

confidence: 85%

“…After morphine treatment, increases in PKC or ERK activities have been reported [44,45]. Although only chronic but not acute treatment of morphine could up-regulate PKA activity [46], all three protein kinases have been shown to phosphorylate OPRM1, thus resulting in receptor desensitization [17,[47][48][49]. Recently, Src activation has also been recognized to be involved in OPRM1 signal regulation [50].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, morphine was unable to induce OPRM1 phosphorylation and βArrs recruitment [3,15,16]. In addition, when Gαi-mediated inhibition of adenylyl cyclase activity was monitored, OPRM1 desensitization was observed only after several hours of DAMGO pretreatment while receptor phosphorylation and βArr recruitment occurred within minutes [8,17]. Moreover, the inability of GRKs and βArr2 overexpression to affect OPRM1 desensitization in various cell types further suggested a lack of correlation between OPRM1 desensitization and GRK-mediated receptor phosphorylation and βArrs recruitment [16,18,19].…”

Section: Introductionmentioning

confidence: 98%

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Morphine-induced μ-opioid receptor rapid desensitization is independent of receptor phosphorylation and β-arrestins

Chu

Zheng

Loh

et al. 2008

Cellular Signalling

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Receptor desensitization involving receptor phosphorylation and subsequent βArrestin (βArr) recruitment has been implicated in the tolerance development mediated by μ-opioid receptor (OPRM1). However, the roles of receptor phosphorylation and βArr on morphine-induced OPRM1 desensitization remain to be demonstrated. Using OPRM1-induced intracellular Ca 2+ ([Ca 2+ ] i ) release to monitor receptor activation, as predicted, [D-Ala 2 , N-Me-Phe 4 , Gly 5 -ol]-enkephalin (DAMGO), induced OPRM1 desensitization in a receptor phosphorylation-and βArr-dependent manner. The DAMGO-induced OPRM1 desensitization was attenuated significantly when phosphorylation deficient OPRM1 mutants or Mouse Embryonic Fibroblast (MEF) cells from βArr1 and 2 knockout mice were used in the studies. Specifically, DAMGO-induced desensitization was blunted in HEK293 cells expressing the OPRM1S375A mutant and was eliminated in MEF cells isolated from βArr2 knockout mice expressing the wild type OPRM1. However, although morphine also could induce a rapid desensitization on [Ca 2+ ] i release to a greater extent than that of DAMGO and could induce the phosphorylation of Ser 375 residue, morphine-induced desensitization was not influenced by mutating the phosphorylation sites or in MEF cells lacking βArr1 and 2. Hence, morphine could induce OPRM1 desensitization via pathway independent of βArr, thus suggesting the in vivo tolerance development to morphine can occur in the absence of βArr.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Morphine-induced μ-opioid receptor rapid desensitization is independent of receptor phosphorylation and β-arrestins

Chu

Zheng

Loh

et al. 2008

Cellular Signalling

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“…De-sensitization can occur in an agonist-dependent (homologous) and agonist-independent (heterologous) manner (For review see (61). While homologous de-sensitization is thought to involve the G protein coupled receptor kinases (GRK) (62-65), heterologous de-sensitization involves PKC mediated phosphorylation of the opioid receptor (62,64,66,67). Both NMDA receptor (68,69) and insulin-induced tyrosine kinase receptor activity (70) have been reported to activate PKC resulting in heterologous de-sensitization of the μ opioid receptor.…”

Section: B the Primary Afferent-spinal Cord Synapsementioning

confidence: 99%

Protein kinase C in pain: Involvement of multiple isoforms

Velázquez

Mohammad

Sweitzer

2007

Pharmacological Research

130

125

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Pain is the primary reason that people seek medical care. At present chronic unremitting pain is the third greatest health problem after heart disease and cancer. Chronic pain is an economic burden in lost wages, lost productivity, medical expenses, legal fees and compensation. Chronic pain is defined as a pain of greater than two months duration and can be of an inflammatory or neuropathic origin that can arise following nerve injury or in the absence of any apparent injury. Chronic pain is characterized by an altered pain perception that includes allodynia (a response to a normally nonnoxious stimuli), and hyperalgesia (an exaggerated response to a normally noxious stimuli). This type of pain is often insensitive to the traditional pain drugs or surgical intervention and thus the study of the cellular and molecular mechanisms that contribute to chronic pain are of the up-most importance for the development of a new generation of analgesic agents. Protein kinase C isozymes are under investigation as potential therapeutics for the treatment of chronic pain conditions. The anatomical localization of protein kinase C isozymes in both peripheral and central nervous system sites that process pain have made them the topic of basic science research for close to two decades. This review will outline the research to date on protein kinase C involvement in pain and analgesia. In addition, this review will try to synthesize these works to begin to develop a comprehensive mechanistic understanding of how protein kinase C may function as the master regulator of peripheral and central sensitization that underlies many chronic pain conditions.

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“…The uncertainty concerning differential efficacy of MOP agonists for G protein activation, rapid desensitization, and endocytosis have probably arisen for three main reasons. First, most studies of these processes have used heterologous expression systems that greatly overexpress receptors, thus disrupting quantitative determination of relative signaling efficacy as well as the stoichiometry of MOP/GRK/␤-arrestin interactions (11,26,27). Second, MOP activation, desensitization, and endocytosis have generally been compared between different cellular expression systems under different conditions (22,24,25).…”

mentioning

confidence: 99%

Opioid Agonists Have Different Efficacy Profiles for G Protein Activation, Rapid Desensitization, and Endocytosis of Mu-opioid Receptors

Borgland

Connor

Osborne

et al. 2003

Journal of Biological Chemistry

144

179

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The differential ability of various -opioid receptor (MOP) agonists to induce rapid receptor desensitization and endocytosis of MOP could arise simply from differences in their efficacy to activate G proteins or, alternatively, be due to differential capacity for activation of other signaling processes. We used AtT20 cells stably expressing a low density of FLAG-tagged MOP to compare the efficacies of a range of agonists to 1) activate G proteins using inhibition of calcium channel currents (I Ca ) as a reporter before and after inactivation of a fraction of receptors by ␤-chlornaltrexamine, 2) produce rapid, homologous desensitization of I Ca inhibition, and 3) internalize receptors. Relative efficacies determined for G protein coupling were [Tyr-D-Ala-Gly-MePhe-Glyol]enkephalin (DAMGO) (1) > methadone (0.98) > morphine (0.58) > pentazocine (0.15). The same rank order of efficacies for rapid desensitization of MOP was observed, but greater concentrations of agonist were required than for G protein activation. By contrast, relative efficacies for promoting endocytosis of MOP were DAMGO (1) > methadone (0.59) > > morphine (0.07) > pentazocine (0.03). These results indicate that the efficacy of opioids to produce activation of G proteins and rapid desensitization is distinct from their capacity to internalize -opioid receptors but that, contrary to some previous reports, morphine can produce rapid, homologous desensitization of MOP.Tolerance to the analgesic and other effects of opioid drugs, such as morphine, undermines their use in long term treatment (1). Although analgesic tolerance is likely to be a complex phenomenon, an understanding of how -opioid (MOP) 1 receptors are regulated by opioid agonists will lead to important insights into this phenomenon. MOPs are similar to many other G protein-coupled receptors (GPCR) in that they undergo desensitization within several minutes of stimulation by agonists (2-4), and continued agonist exposure results in removal of receptors from the cell surface (5-7). MOP phosphorylation is increased as a consequence of agonist exposure, leading to a commonly held assumption that receptor phosphorylation is essential for MOP desensitization and internalization (5, 8 -10). The mechanism that may be responsible for uncoupling MOP from G protein activation and then promoting receptor sequestration is as follows: phosphorylation of the agonist occupied MOP by a G protein receptor kinase (GRK), subsequent binding of ␤-arrestins to the phosphorylated receptor, and removal of MOP from the cell surface via a clathrin-dependent process (11-15). The enhanced analgesic potency of morphine and diminished analgesic tolerance in ␤-arrestin2 knockout mice suggest that the capacity of opioid agonists to cause receptor desensitization and endocytosis is one of the key cellular mechanisms underlying tolerance (16). Phosphorylation of MOP by protein kinase C (PKC) or calmodulin-dependent kinase II can also reduce the capacity of MOP to activate G proteins (8,17), also contributing to opioid tole...

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The Absence of a Direct Correlation between the Loss of [d-Ala2,MePhe4,Gly5-ol]Enkephalin Inhibition of Adenylyl Cyclase Activity and Agonist-induced μ-Opioid Receptor Phosphorylation

Cited by 55 publications

References 34 publications

Morphine-induced μ-opioid receptor rapid desensitization is independent of receptor phosphorylation and β-arrestins

Morphine-induced μ-opioid receptor rapid desensitization is independent of receptor phosphorylation and β-arrestins

Protein kinase C in pain: Involvement of multiple isoforms

Opioid Agonists Have Different Efficacy Profiles for G Protein Activation, Rapid Desensitization, and Endocytosis of Mu-opioid Receptors

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