Cys-27 Variant of Human δ-Opioid Receptor Modulates Maturation and Cell Surface Delivery of Phe-27 Variant via Heteromerization

Leskelä, Tarja T.; Lackman, Jarkko J.; Vierimaa, Miia M.; Kobayashi, Hiroyuki; Bouvier, Michel; Petäjä-Repo, Ulla E.

doi:10.1074/jbc.m111.305656

Cited by 19 publications

(10 citation statements)

References 54 publications

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“…For example, the in vitro dominant negative effects of the retinitis pigmentosa causative rhodopsin mutant P23H, is suppressed by retinoids acting as PCs [63]. Furthermore, the human δ opioid receptor variant Cys-27 exerts a dominant negative effect on the Phe-27 variant, impairing its maturation and targeting it for degradation, an effect that can be overcome by the opioid receptor antagonist naltrexone [64]. The dominant negative effect of a α (1b) -adrenoceptor transmembrane mutant on wild type α (1b) -adrenoceptor can be rescued by α (1b) -adrenoceptor antagonists, requiring only PC binding to the mutant receptor and not the wild type receptor [58].…”

Section: Structural Mechanismsmentioning

confidence: 99%

“…One of the best studied compounds in this regard is the nACh receptor agonist nicotine, the chaperoning activity of which is thought to contribute to the addictive properties of nicotine, as well as to its therapeutic effect on Parkinson’s disease and potential to treat epilepsy associated with nACh receptor mutants [5]. Other central nervous system proteins that likely undergo in vivo chaperoning include multiple types of opioid receptors which are chaperoned in vitro by a variety of clinically used opioids [64,122,128,129]. Furthermore, antipsychotics that bind to dopamine D 2–4 receptors are potent chaperones of dopamine D4 receptor folding mutants, as well as wild type D4 receptors [130,131].…”

Section: Unrecognized Pharmacological Chaperoningmentioning

confidence: 99%

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Pharmacological chaperoning: A primer on mechanism and pharmacology

Leidenheimer

Ryder

2014

Pharmacological Research

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Approximately forty percent of diseases are attributable to protein misfolding, including those for which genetic mutation produces misfolding mutants. Intriguingly, many of these mutants are not terminally misfolded since native-like folding, and subsequent trafficking to functional locations, can be induced by target-specific, small molecules variably termed pharmacological chaperones, pharmacoperones, or pharmacochaperones (PCs). PC targets include enzymes, receptors, transporters, and ion channels, revealing the breadth of proteins that can be engaged by ligand-assisted folding. The purpose of this review is to provide an integrated primer of the diverse mechanisms and pharmacology of PCs. In this regard, we examine the structural mechanisms that underlie PC rescue of misfolding mutants, including the ability of PCs to act as surrogates for defective intramolecular interactions and, at the intermolecular level, overcome oligomerization deficiencies and dominant negative effects, as well as influence the subunit stoichiometry of heteropentameric receptors. Not surprisingly, PC-mediated structural correction of misfolding mutants normalizes interactions with molecular chaperones that participate in protein quality control and forward-trafficking. A variety of small molecules have proven to be efficacious PCs and the advantages and disadvantages of employing orthostatic antagonists, active-site inhibitors, orthostatic agonists, and allosteric modulator PCs is considered. Also examined is the possibility that several therapeutic agents may have unrecognized activity as PCs, and this chaperoning activity may mediate/contribute to therapeutic action and/or account for adverse effects. Lastly, we explore evidence that pharmacological chaperoning exploits intrinsic ligand-assisted folding mechanisms. Given the widespread applicability of PC rescue of mutants associated with protein folding disorders, both in vitro and in vivo, the therapeutic potential of PCs is vast. This is most evident in the treatment of lysosomal storage disorders, cystic fibrosis, and nephrogenic diabetes insipidus, for which proof of principle in humans has been demonstrated.

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Section: Structural Mechanismsmentioning

confidence: 99%

Section: Unrecognized Pharmacological Chaperoningmentioning

confidence: 99%

Pharmacological chaperoning: A primer on mechanism and pharmacology

Leidenheimer

Ryder

2014

Pharmacological Research

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“…2) (Gelernter and Kranzler, 2000). Both alleles of the nonsynonymous mutations display similar pharmacological and signaling properties (Leskelä et al, 2009), but their maturation and ligandindependent trafficking differ (Leskelä et al, 2009(Leskelä et al, , 2012Sarajärvi et al, 2011). Thus, the least frequent variant Cys27 (Gelernter and Kranzler, 2000) displays greater precursor retention in the ER and enhanced turnover of mature surface receptors compared with the more common Phe27 allele (Leskelä et al, 2009).…”

Section: B Alterations To D-opioid Receptor Primary Structure: Polymmentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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“…It can be speculated that the unpaired Cys residue of the h␦OR Cys 27 variant and the interactions that it mediates could hinder receptor dimerization in the ER. This would give an explanation to our recent finding that in co-expressed cells, the Cys 27 variant was found to target part of the Phe 27 variant to ERAD in a dominant negative man-ner (48). The heterodimers might be less likely to oligomerize properly compared with the h␦OR-Phe 27 homodimers, thus failing to pass the QC checkpoints.…”

Section: Discussionmentioning

confidence: 91%

N-Glycan-dependent and -independent Quality Control of Human δ Opioid Receptor N-terminal Variants

Lackman

Markkanen

Hogue

et al. 2014

Journal of Biological Chemistry

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Background: ␦-Opioid receptor (␦OR) F27C polymorphism affects receptor cell surface targeting. Results: If lacking N-glycans, Cys 27 , but not Phe 27 , is extensively targeted to endoplasmic reticulum-associated degradation and can escape to the cell surface in nonnative conformation. Conclusion: ␦OR relies on N-glycan-dependent calnexin-mediated quality control (QC) for correct folding, whereas N-glycanindependent QC is a backup system. Significance: Alternative QC pathways monitor nascent GPCRs.

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Cys-27 Variant of Human δ-Opioid Receptor Modulates Maturation and Cell Surface Delivery of Phe-27 Variant via Heteromerization

Cited by 19 publications

References 54 publications

Pharmacological chaperoning: A primer on mechanism and pharmacology

Pharmacological chaperoning: A primer on mechanism and pharmacology

Molecular Pharmacology ofδ-Opioid Receptors

N-Glycan-dependent and -independent Quality Control of Human δ Opioid Receptor N-terminal Variants

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