Opioid receptor endocytosis and activation of MAP kinase pathway

Trapaidze, Nino; Gomes, Ivone; Cvejic, Svetlana; Bansinath, M.; Devi, Lakshmi A.

doi:10.1016/s0169-328x(00)00002-4

Cited by 69 publications

(50 citation statements)

References 40 publications

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“…Furthermore, opioid-mediated desensitization/resensitization of the MAPK pathway has not been well explored. We have found that activation of all three opioid receptor types (mu, delta, and kappa) by agonists results in the rapid phosphorylation of MAPKs (this study; Trapaidze et al, 2000b;Jordan et al, 2000). Furthermore, on receptor internalization, the level of MAPK phosphorylation is significantly reduced in the case of mu and delta receptors (Trapaidze et al, 2000b).…”

Section: Discussionsupporting

confidence: 58%

Recycling and Resensitization of Delta Opioid Receptors

Trapaidze

Gomes²,

Bansinath³

et al. 2000

DNA and Cell Biology

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Exposure to opioids results in the activation of opioid receptors; this is follow ed by receptor endocytosis. Previously, we showed that delta opioid receptors undergo rapid agonist-mediated internalization and that mutations in the C-tail result in a substantial loss of agonist-mediated internalization. In this study, we investigated the fate of receptors following rapid internalization. We found that the majority of the wild type receptors recycled back to the surface after acute agonist treatment. The kinetics of internalization and recycling of the receptor were virtually identical to the kinetics of internalization and recycling of the radiolabeled agonist. In contrast, the kinetics of internalization and recycling of a C-tail mutant receptor were substantially altered, suggesting an involvement of the C-tail in the recycling process. It is possible that in addition to agonist-mediated internalization, opioid receptors undergo constitutive, agonist-independent internalization. We directly examined this possibility using an antibody-prebinding assay. The wild type delta opioid receptors exhibited agonist-independent internalization via the clathrincoated pit pathway. We also examined the role of receptor internalization and recycling in the modulation of its function by quantitating the level of opioid-stimulated phosphorylation of MAP kinase (MAPK) under conditions of receptor internalization and recycling. We found that agonist treatment caused a rapid increase in the level of phosphorylated MAPK that was rapidly desensitized. The removal of the agonist, which results in receptor recycling, led to the resensitization of the receptor, as evidenced by the agonist's ability to reinduce MAPK phosphorylation. Mutant receptors that underwent rapid recycling exhibited enhanced resensitization, suggesting a role for receptor recycling in the re-sensitization process. Taken together, these results indicate that agonist-mediated internalization and recycling modulate opioid receptor function and that the receptor C-tail plays an important role in both processes.

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Section: Discussionsupporting

confidence: 58%

Recycling and Resensitization of Delta Opioid Receptors

Trapaidze

Gomes²,

Bansinath³

et al. 2000

DNA and Cell Biology

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“…Previous reports show no effects of mutated or truncated COOH termini of opioid receptors on desensitization and/or internalization of these receptors (22,36,45,46). These studies raise the fundamental question of whether or not phosphorylation is actually required for agonist-induced desensitization and internalization of opioid receptors.…”

Section: Discussionmentioning

confidence: 64%

“…The same study shows that a truncated mutant at position 354 internalized constitutively and that receptor internalization is enhanced in presence of DAMGO (14). Similarly, Trapaidze et al (46) have shown that a truncated MOR lacking Thr 394 continued to internalize in response to DAMGO but not the mutant lacking the last COOH-terminal 24 amino acids. Consistent with our findings, these results indicate the presence of positive and negative endocytotic signals within the C-tail of MOR.…”

Section: Discussionmentioning

confidence: 83%

Phosphorylation of Ser363, Thr370, and Ser375 Residues within the Carboxyl Tail Differentially Regulates μ-Opioid Receptor Internalization

Kouhen

Burd

Erickson-Herbrandson

et al. 2001

Journal of Biological Chemistry

117

126

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Prolonged activation of opioid receptors leads to their phosphorylation, desensitization, internalization, and down-regulation. To elucidate the relationship between -opioid receptor (MOR) phosphorylation and the regulation of receptor activity, a series of receptor mutants was constructed in which the 12 Ser/Thr residues of the COOH-terminal portion of the receptor were substituted to Ala, either individually or in combination. All these mutant constructs were stably expressed in human embryonic kidney 293 cells and exhibited similar expression levels and ligand binding properties. to Ala accelerated MOR internalization kinetics. The present data show that the basal phosphorylation of MOR could play a role in modulating agonist-induced receptor internalization kinetics. Furthermore, even though -receptors and ␦-opioid receptors have the same motif encompassing agonist-induced phosphorylation sites, the different agonist-induced internalization properties controlled by these sites suggest differential cellular regulation of these two receptor subtypes.Opioid alkaloids, as well as endogenous opioid peptides, exert their multiple biological effects on target tissues by interacting with specific cell surface receptors including the ␦-, -, and -opioid receptors (1). These opioid receptors belong to the superfamily of G protein-coupled receptors (GPCRs).1 The -opioid receptor (MOR) serves as the principle physiological target for most clinically important opioid analgesics, such as morphine and fentanyl (2, 3). Although many opioid alkaloids exert their pharmacological effects via MOR, their binding affinity for the receptor and potency to activate the receptor do not always correspond to their abilities to induce tolerance (4 -8). This suggests that other cellular processes that modulate MOR responsiveness, such as receptor desensitization and internalization, may contribute to opioid tolerance and dependence. Like many other GPCRs, opioid receptors are regulated by agonist-dependent processes and undergo receptor phosphorylation, desensitization, internalization, and down-regulation (1). Interestingly, in addition to the subtype-specific regulation of opioid receptors (9 -12), individual opioid receptors are differentially regulated by distinct opioid agonists (5-8, 13, 14). In the case of MOR, opioid agonists demonstrating equivalent ability to activate receptor signaling exhibit remarkable differences in their abilities to functionally desensitize (5, 6) and induce internalization of the receptor in both transfected cells and neurons (7,8,(13)(14)(15). However, the detailed molecular events underlying this differential regulation of MOR by distinct agonists remain unclear. Using chimeric, truncated, or mutated opioid receptors, several studies reported the crucial role of the C-tail of opioid receptors in regulating their activities and trafficking (11, 16 -20). Whereas several potential phosphorylation sites were suggested to be involved in regulating the activity and trafficking of opioid receptors, the actual ...

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“…CHO or HEK-293 cells expressing hκOR, hμOR, or hδOR (2 × 10 5 cells per well) were treated with vehicle or κOR ligands (10 −13 -10 −6 M) for 3 min at 37°C. ERK1/2 phosphorylation and Akt phosphorylation at S473 or T308 were measured by Western blot as previously described (36,37).…”

Section: Methodsmentioning

confidence: 99%

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Gupta

Gomes

Bobeck

et al. 2016

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

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Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum. Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10-to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non-histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects.G-protein-coupled receptors | natural compounds | salvinorin A | dynorphin | antinociception

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Opioid receptor endocytosis and activation of MAP kinase pathway

Cited by 69 publications

References 40 publications

Recycling and Resensitization of Delta Opioid Receptors

Recycling and Resensitization of Delta Opioid Receptors

Phosphorylation of Ser363, Thr370, and Ser375 Residues within the Carboxyl Tail Differentially Regulates μ-Opioid Receptor Internalization

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

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