Role of carboxyl terminus of μ- and δ-opioid receptor in agonist -induced down-regulation

Afify, Elham A.; Law, Ping Yee; Riedl, Maureen; Elde, Robert; Loh, Horace H.

doi:10.1016/s0169-328x(97)00315-x

Cited by 42 publications

(47 citation statements)

References 29 publications

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“…The coding sequences of M6a, M6b (GI: 9502118), and DM20 were amplified by PCR and then subcloned into the pGEM-T easy vector (Promega) for producing relative riboprobes. Generation of 35 S-labeled and digoxigeninlabeled riboprobes, hybridization, washing procedures, and detection of hybridization signals were performed as described (20). Hybridization signal densities of the sense probes were defined as background levels.…”

Section: Methodsmentioning

confidence: 99%

Membrane Glycoprotein M6a Interacts with the μ-Opioid Receptor and Facilitates Receptor Endocytosis and Recycling

Koch

Liang

et al. 2007

Journal of Biological Chemistry

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Using a yeast two-hybrid screen, the neuronal membrane glycoprotein M6a, a member of the proteolipid protein family, was identified to be associated with the -opioid receptor (MOPr). Bioluminescence resonance energy transfer and co-immunoprecipitation experiments confirmed that M6a interacts agonist-independently with MOPr in human embryonic kidney 293 cells co-expressing MOPr and M6a. Co-expression of MOPr with M6a, but not with M6b or DM20, exists in many brain regions, further supporting a specific interaction between MOPr and M6a. After opioid treatment M6a co-internalizes and then co-recycles with MOPr to cell surface in transfected human embryonic kidney 293 cells. Moreover, the interaction of M6a and MOPr augments constitutive and agonist-dependent internalization as well as the recycling rate of -opioid receptors. On the other hand, overexpression of a M6a-negative mutant prevents -opioid receptor endocytosis, demonstrating an essential role of M6a in receptor internalization. In addition, we demonstrated the interaction of M6a with a number of other G protein-coupled receptors (GPCRs) such as the ␦-opioid receptor, cannabinoid receptor CB1, and somatostatin receptor sst2A, suggesting that M6a might play a general role in the regulation of certain GPCRs. Taken together, these data provide evidence that M6a may act as a scaffolding molecule in the regulation of GPCR endocytosis and intracellular trafficking.The clinical utility of opiates is greatly limited by adaptive changes in the nervous system causing tolerance, dependence, and addiction. These adaptive changes are initiated by binding of opiate drugs to opioid receptors that are also activated by endogenous opioid peptides (1). The -opioid receptor mediates the analgesic effects of opioids but is also important for initiating adaptive changes in the nervous system causing opioid tolerance, dependence, and addiction (2-4). On the cellular level, the repeated opioid exposure induces a rapid phosphorylation of intracellular receptor domains, leading to receptor desensitization followed by receptor internalization (5). Internalized receptors can be sorted either to a degradative pathway for down-regulation or recycling pathway for reactivation (6). There is increasing evidence that the trafficking and signaling of opioid receptors are regulated by direct interaction with membranal and/or cytosolic proteins (7).In the course of identifying new -opioid receptor-interacting proteins using a yeast two-hybrid method, we isolated a cDNA encoding for the membrane glycoprotein M6a. M6a is a member of the proteolipid protein (PLP) 2 family of tetraspan membrane proteins and mainly expressed in neurons (8 -10). M6a shares 40% homology with DM20, the smaller splice isoform of the major central nervous system myelin proteolipid PLP, which is mainly expressed in myelinating glial cells (11). M6a is 55% homologous to proteolipid M6b, which is expressed in neurons and oligodendrocytes (8,9,12). M6a is suggested to play a role as a modulator for neurite outgrowth (13) ...

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Section: Methodsmentioning

confidence: 99%

Membrane Glycoprotein M6a Interacts with the μ-Opioid Receptor and Facilitates Receptor Endocytosis and Recycling

Koch

Liang

et al. 2007

Journal of Biological Chemistry

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“…On the contrary, MOR is uncapable of interacting with GASP and rapidly recycles back to the plasma membrane after activation [45]. Exchanging the cytoplasmic tail of DOR with that of MOR swapped the postendocytic sorting profiles of the receptors [44,46]. Therefore, we used these chimeric receptors (DORMT, DOR with the C-terminal tail of MOR, and MORDT, MOR with the C-terminal tail of DOR) to test whether different endocytic and postendocytic behaviors of the receptors are linked to the regulation of BACE1 and γ-secretase.…”

Section: Postendocytic Sorting Of Activated Dor Defines β-And γ-Secrementioning

confidence: 99%

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

et al. 2010

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Dysregulation of β-site APP-cleaving enzyme (BACE) and/or γ-secretase leads to anomalous production of amyloid-β peptide (Aβ) and contributes to the etiology of Alzheimer's disease (AD). Since these secretases mediate proteolytic processing of numerous proteins, little success has been achieved to treat AD by secretase inhibitors because of inevitable undesired side effects. Thus, it is of importance to unravel the regulatory mechanisms of these secretases. Here, we show that δ-opioid receptor (DOR) promotes the processing of Aβ precursor protein (APP) by BACE1 and γ-secretase, but not that of Notch, N-cadherin or APLP. Further investigation reveals that DOR forms a complex with BACE1 and γ-secretase, and activation of DOR mediates the co-endocytic sorting of the secretases/ receptor complex for APP endoproteolysis. Dysfunction of the receptor retards the endocytosis of BACE1 and γ-secretase and thus the production of Aβ. Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Aβ pathology and Aβ-dependent behavioral deficits, but does not affect the processing of Notch, N-cadherin or APLP in AD model mice. Our study not only uncovers a molecular mechanism for the formation of a DOR/secretase complex that regulates the specificity of secretase for Aβ production but also suggests that intervention of either formation or trafficking of the GPCR/secretase complex could lead to a new strategy against AD, potentially with fewer side effects.

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“…The receptors with stronger signals for recycling than those for degradation, such as the ␤ 2 -AR, will be predominantly recycled with a low extent of down-regulation (5,35). Those that provide stronger signals for the lysosomal pathway than for the recycling, such as protease-activated receptor 1 and the ␦ opioid receptor, will be mainly degraded in lysosomes (5,6,8,9). The hkor appears to be intermediate of the two extreme cases, having signals for the lysosomal pathway and interacting with the recycling mechanism.…”

Section: Ebp50/nherf Interacts With the C Terminus Of The Hkor-mentioning

confidence: 99%

“…Alternatively, receptors are trafficked to lysosomes or proteasomes where proteolytic degradation of the receptor occurs, leading to down-regulation. Following internalization, some GPCRs, such as ␤ 2 -adrenergic receptor (␤ 2 -AR) and substance P receptor, are predominantly recycled to plasma membranes (5,6), whereas some others, such as protease-activated receptor 1 and ␦ opioid receptor, are mostly trafficked to lysosomes for degradation (5)(6)(7)(8)(9). The signals that direct the trafficking of internalized receptors to the recycling or the down-regulation pathway have not been fully elucidated.…”

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confidence: 99%

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Ezrin-Radixin-Moesin-binding Phosphoprotein-50/Na+/H+ Exchanger Regulatory Factor (EBP50/NHERF) Blocks U50,488H-induced Down-regulation of the Human κ Opioid Receptor by Enhancing Its Recycling Rate

Chen

Liu‐Chen

2002

Journal of Biological Chemistry

111

115

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We have investigated whether Ezrin-radixin-moesin (ERM)-binding phosphoprotein-50/Na؉ /H ؉ exchanger regulatory factor (EBP50/NHERF), a PDZ domain-containing phosphoprotein, is associated with the human opioid receptor (hkor) and whether it regulates the trafficking and signaling of the hkor. To determine the motif of FLAG-hkor involved in EBP50/NHERF binding, we generated two mutants, FLAG-hkor-A and FLAG-hkor-EE, in which one Ala or two Glu residues were added to the C terminus, respectively. Neither FLAG-hkor-A nor FLAG-hkor-EE co-immunoprecipitated with EBP50/NHERF, and U50,488H-induced down-regulation of FLAG-hkor-A and FLAG-hkor-EE were not affected by expression of EBP50/NHERF. Thus, EBP50/NHERF binds to the C terminus of FLAG-hkor and blocks the down-regulation of FLAG-hkor. The C-terminal sequence of the hkor, NKPV, is distinctly different from the sequence D(S/T)XL, the optimal C-terminal motif in the ␤ 2 -adrenergic receptor for EBP50/NHERF binding. EBP50/NHERF may have a broader binding specificity and may interact with a subset of G protein-coupled receptors to serve as a recycling signal for these receptors.

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Role of carboxyl terminus of μ- and δ-opioid receptor in agonist -induced down-regulation

Cited by 42 publications

References 29 publications

Membrane Glycoprotein M6a Interacts with the μ-Opioid Receptor and Facilitates Receptor Endocytosis and Recycling

Membrane Glycoprotein M6a Interacts with the μ-Opioid Receptor and Facilitates Receptor Endocytosis and Recycling

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

Ezrin-Radixin-Moesin-binding Phosphoprotein-50/Na+/H+ Exchanger Regulatory Factor (EBP50/NHERF) Blocks U50,488H-induced Down-regulation of the Human κ Opioid Receptor by Enhancing Its Recycling Rate

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