Morphine Promotes Rapid, Arrestin-Dependent Endocytosis of μ-Opioid Receptors in Striatal Neurons

Haberstock-Debić, Helena; Kim, Kyung-Ah; Yu, Yang; Zastrow, Mark von

doi:10.1523/jneurosci.5045-04.2005

Cited by 132 publications

(128 citation statements)

References 45 publications

(60 reference statements)

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“…Many cell culture studies have manipulated kinase or ␤-arrestin expression to alter morphine-induced MOR trafficking. In neurons, Haberstock-Debic et al (44,45) showed that morphine-induced MOR trafficking differs between neurons and even within different regions of the same neuron. MOR trafficking was observed in the dendrites of nucleus accumbens neurons but not in the soma of the same neurons (45).…”

Section: Discussionmentioning

confidence: 99%

Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation

Groer

Schmid

Jaeger

et al. 2011

Journal of Biological Chemistry

115

112

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Morphine and other opiates mediate their effects through activation of the -opioid receptor (MOR), and regulation of the MOR has been shown to critically affect receptor responsiveness. Activation of the MOR results in receptor phosphorylation, ␤-arrestin recruitment, and internalization. This classical regulatory process can differ, depending on the ligand occupying the receptor. There are two forms of ␤-arrestin, ␤-arrestin1 and ␤-arrestin2 (also known as arrestin2 and arrestin3, respectively); however, most studies have focused on the consequences of recruiting ␤-arrestin2 specifically. In this study, we examine the different contributions of ␤-arrestin1-and ␤-arrestin2-mediated regulation of the MOR by comparing MOR agonists in cells that lack expression of individual or both ␤-arrestins. Here we show that morphine only recruits ␤-arrestin2, whereas the MOR-selective enkephalin [D-Ala 2 ,N-MePhe 4 ,Gly 5 -ol]enkephalin (DAMGO), recruits either ␤-arrestin. We show that ␤-arrestins are required for receptor internalization and that only ␤-arrestin2 can rescue morphine-induced MOR internalization, whereas either ␤-arrestin can rescue DAMGO-induced MOR internalization. DAMGO activation of the receptor promotes MOR ubiquitination over time. Interestingly, ␤-arrestin1 proves to be critical for MOR ubiquitination as modification does not occur in the absence of ␤-arrestin1 nor when morphine occupies the receptor. Moreover, the selective interactions between the MOR and ␤-arrestin1 facilitate receptor dephosphorylation, which may play a role in the resensitization of the MOR and thereby contribute to overall development of opioid tolerance.Morphine and other opiates are among the most clinically useful analgesics, and their actions are mediated largely through activation of -opioid receptors (MORs).3 As a G protein-coupled receptor (GPCR), the MOR is subject to regulation paradigms that include phosphorylation by GPCR kinases (GRKs) and subsequent interactions with ␤-arrestins (␤-arrestin1, also known as arrestin2, and ␤-arrestin2, also known as arrestin3). ␤-Arrestins can then initiate receptor internalization, which in turn can promote both receptor down-regulation and resensitization (1-3). ␤-Arrestins can also facilitate these regulatory events by scaffolding ubiquitination machinery, such as E3 ligases, to GPCRs, as has been shown for the ␤ 2 adrenergic receptor (␤ 2 AR), V2 vasopressin receptor, and the chemokine receptor (CXCR4) (4 -6), however this has not been demonstrated for the MOR. MOR regulation has been shown to be contingent upon the particular agonist acting at the receptor as morphine promotes different regulatory events than other opioid ligands, including the D-enkephalin analog, [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]enkephalin (DAMGO), fentanyl, methadone, and etorphine, although all of these ligands are full agonists at the MOR with respect to G protein coupling (7). The difference between agonists was first recognized when Arden et al. (8) observed that although DAMGO promotes robust internalizatio...

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Section: Discussionmentioning

confidence: 99%

Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation

Groer

Schmid

Jaeger

et al. 2011

Journal of Biological Chemistry

115

112

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“…Morphine-stimulated MORs have been shown, with few exceptions (41,42), to elude internalization (43). It has been suggested that this aberrant trafficking of MORs results in prolonged activation of the MORs, leading to compensatory changes that result in tolerance to morphine.…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of human variants of the mu-opioid receptor gene

Ravindranathan

Joslyn

Robertson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Opioids and their receptors have an important role in analgesia and alcohol and substance use disorders (ASUD). We have identified several naturally occurring amino acid changing variants of the human mu-opioid receptor (MOR), and assessed the functional consequences of these previously undescribed variants in stably expressing cell lines. Several of these variants had altered trafficking and signaling properties. We found that an L85I variant showed significant internalization in response to morphine, in contrast to the WT MOR, which did not internalize in response to morphine. Also, when L85I and WT receptor were coexpressed, WT MOR internalized with the L85I MOR, suggesting that, in the heterozygous condition, the L85I phenotype would be dominant. This finding is potentially important, because receptor internalization has been associated with development of tolerance to opiate analgesics. In contrast, an R181C variant abolished both signaling and internalization in response to saturating doses of the hydrolysis-resistant enkephalin [D-Ala2,N-MePhe4,Gly5-ol]enkephalin (DAMGO). Coexpression of the R181C and WT receptor led to independent trafficking of the 2 receptors. S42T and C192F variants showed a rightward shift in potency of both morphine and DAMGO, whereas the S147C variant displayed a subtle leftward shift in morphine potency. These data suggest that these and other such variants may have clinical relevance to opioid responsiveness to both endogenous ligands and exogenous drugs, and could influence a broad range of phenotypes, including ASUD, pain responses, and the development of tolerance to morphine.OPRM1 ͉ SNP ͉ tolerance ͉ morphine ͉ opiate

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“…However, two recent studies provided evidence that desensitization and endocytosis of MOR occurred with morphine treatment (17,18). Activation of ERK1/2 by the mu opioid agonist DAMGO has been demonstrated in MOR-transfected cells and in neurons from morphine-treated mice (8,9).…”

Section: Discussionmentioning

confidence: 99%

Mu Opioid Receptor Activation of ERK1/2 Is GRK3 and Arrestin Dependent in Striatal Neurons

Macey

Lowe

Chavkin

2006

Journal of Biological Chemistry

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In this study we investigated the mechanisms responsible for MAP kinase ERK1/2 activation following agonist activation of endogenous mu opioid receptors (MOR) normally expressed in cultured striatal neurons. Treatment with the MOR agonist fentanyl caused significant activation of ERK1/2 in neurons derived from wild type mice. Fentanyl effects were blocked by the opioid antagonist naloxone and were not evident in neurons derived from MOR knock-out (؊/؊) mice. In contrast, ERK1/2 activation by fentanyl was not evident in neurons from GRK3 ؊/؊ mice or neurons pretreated with small inhibitory RNA for arrestin3. Consistent with this observation, treatment with the opiate morphine (which is less able to activate arrestin) did not elicit ERK1/2 activation in wild type neurons; however, transfection of arrestin3-(R170E) (a dominant positive form of arrestin that does not require receptor phosphorylation for activation) enabled morphine activation of ERK1/2. In addition, activation of ERK1/2 by fentanyl and morphine was rescued in GRK3 ؊/؊ neurons following transfection with dominant positive arrestin3-(R170E). The activation of ERK1/2 appeared to be selective as p38 MAP kinase activation was not increased by either fentanyl or morphine treatment in neurons from wild type, MOR ؊/؊ , or GRK3 ؊/؊ mice. In addition, U0126 (a selective inhibitor of MEK kinase responsible for ERK phosphorylation) blocked ERK1/2 activation by fentanyl. These results support the hypothesis that MOR activation of ERK1/2 requires opioid receptor phosphorylation by GRK3 and association of arrestin3 to initiate the cascade resulting in ERK1/2 phosphorylation in striatal neurons.Opioid receptor activation results in both acute and longlasting changes in neuronal physiology. The mechanisms responsible for the acute changes include G␣ i/o and G␤␥ protein activation that increases potassium conductance, decreases calcium conductance, and results in presynaptic inhibition (1-3). The mechanisms responsible for the long lasting effects of opioids are less clear but may include changes in adenylyl cyclase activity and activation of mitogen activating protein kinase (MAPK) 2 pathways (4, 5). In this study we used primary cultured neurons isolated from mouse striata to address the mechanisms linking mu opioid receptor (MOR) activation to the phosphorylation and activation of the extracellular signal-related kinases 1 and 2 (ERK1/2) members of the MAPK family. Phosphorylation of ERK1/2 by GPCRs involves growth factor receptor transactivation (4). As demonstrated for the ␤-adrenergic receptor, participation of arrestin is an integral part of GPCR signaling through the ERK1/2 signaling pathway in transfected HEK293 cells (6). Following agonist activation of MOR, the receptor becomes phosphorylated by G-protein receptor kinase (GRK), which initiates an arrestin-dependent desensitization process that involves clathrin-mediated endocytosis (7). The opioid activation of ERK1/2 by MOR agonist (D-Ala 2 ,Me-Phe 4 ,Gly-ol5) (DAMGO) was demonstrated in MOR-transfected c...

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Morphine Promotes Rapid, Arrestin-Dependent Endocytosis of μ-Opioid Receptors in Striatal Neurons

Cited by 132 publications

References 45 publications

Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation

Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation

Functional characterization of human variants of the mu-opioid receptor gene

Mu Opioid Receptor Activation of ERK1/2 Is GRK3 and Arrestin Dependent in Striatal Neurons

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