Influence of the antipsychotic drug pipamperone on the expression of the dopamine D4 receptor

Craenenbroeck, Kathleen Van; Gellynck, Evelien; Lintermans, Béatrice; Leysen, Josée E.; Tol, Hubert H.M. Van; Haegeman, Guy; Vanhoenacker, Peter

doi:10.1016/j.lfs.2006.08.024

Cited by 16 publications

(17 citation statements)

References 40 publications

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“…We have shown previously that chemical (dimethylsulfoxide, glycerol) and pharmacological (receptor ligands) chaperones can help in the folding procedure of the receptor in the ER, thereby decreasing receptor degradation in the proteasome and enhancing expression on the plasma membrane. The pharmacological chaperone quinpirole (a D 2 ‐like receptor agonist) clearly enhances the expression not only of wild‐type D 4.4 R, but also of the folding mutant D 4.4 M345 R. This folding mutant D 4.4 M345 R does not meet the quality control of the ER and is routed to the proteasome for degradation [29,30]. We used this folding mutant to investigate the role of oligomerization in D 4.4 M345 R folding and subsequent plasma membrane expression.…”

Section: Resultsmentioning

confidence: 99%

Dopamine D₄ receptor oligomerization – contribution to receptor biogenesis

et al. 2011

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Dopamine D 4 receptors (D 4 Rs) are G protein-coupled receptors that play a role in attention and cognition. In the present study, we investigated the dimerization properties of this receptor. Western blot analysis of the human D 4.2 R, D 4.4 R and D 4.7 R revealed the presence of higher molecular weight immunoreactive bands, which might indicate the formation of receptor dimers and multimers. Homo-and heterodimerization of the receptors was confirmed by co-immunoprecipitation and bioluminescence resonance energy transfer studies. Although dimerization of a large number of G protein-coupled receptors has been described, the functional importance often remains to be elucidated. Folding efficiency is rate-limiting for D 4 R biogenesis and quality control in the endoplasmic reticulum plays an important role for D 4 R maturation. Co-immunoprecipitation and immunofluorescence microscopy studies using wild-type and a nonfunctional D 4.4 R folding mutant show that oligomerization occurs in the endoplasmic reticulum and that this plays a role in the biogenesis and cell surface targeting of the D 4 R. The different polymorphic repeat variants of the D 4 R display differential sensitivity to the chaperone effect. In the present study, we show that this is also reflected by bioluminescence resonance energy transfer saturation assays, suggesting that the polymorphic repeat variants have different relative affinities to form homo-and heterodimers. In summary, we conclude that D 4 Rs form oligomers with different affinities and that dimerization plays a role in receptor biogenesis.Structured digital abstract l D4.4R physically interacts with D4.2R by anti tag coimmunoprecipitation (View interaction) l D4.xR physically interacts with D4.4R by anti tag coimmunoprecipitation (View interaction) l D4.xR and D4.xR physically interact by bioluminescence resonance energy transfer (View interaction)Abbreviations BRET, bioluminescence resonance energy transfer; CHO, Chinese hamster ovary; DAPI, 4¢,6-diamidino-2-phenylindole; D n R, dopamine D n receptor; ER, endoplasmic reticulum; GPCR, G protein-coupled receptor; HRP, horseradish peroxidase; MP, milk powder; YFP, yellow fluorescent protein.

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Section: Resultsmentioning

confidence: 99%

Dopamine D₄ receptor oligomerization – contribution to receptor biogenesis

et al. 2011

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“…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]. Such chaperoning activity may explain the paradoxical upregulation of D2 receptors by both receptor agonists and antagonists.…”

Section: Unrecognized Pharmacological Chaperoningmentioning

confidence: 99%

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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“…PCs also appear to form the mechanistic basis of action for two drugs used to treat human genetic diseases. Antipsychotics pipamperone and quinparole, which are known D2 ⁄ D3 dopamine receptor antagonists, increase the surface expression of wild-type D4 dopamine receptors [23]. Significantly, the surface expression of the longer polymorphic variants of the D4 receptor, found in patients with attention deficit disorders and hyperactivity, is enhanced by the antipsychotics to a greater degree relative to shorter variants, offering a potential explanation of the differential response of these patients to treatment [24].…”

Section: Screening Libraries For Hexosaminidase Enhancersmentioning

confidence: 99%

Lending a helping hand, screening chemical libraries for compounds that enhance β‐hexosaminidase A activity in GM2 gangliosidosis cells

Tropak

Mahuran

2007

The FEBS Journal

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Enzyme enhancement therapy is an emerging therapeutic approach that has the potential to treat many genetic diseases. Candidate diseases are those associated with a mutant protein that has difficulty folding and/or assembling into active oligomers in the endoplasmic reticulum. Many lysosomal storage diseases are candidates for enzyme enhancement therapy and have the additional advantage of requiring only 5–10% of normal enzyme levels to reduce and/or prevent substrate accumulation. Our long experience in working with the β‐hexosaminidase (EC 3.2.1.52) isozymes system and its associated deficiencies (Tay‐Sachs and Sandhoff disease) lead us to search for possible enzyme enhancement therapy‐agents that could treat the chronic forms of these diseases which express 2–5% residual activity. Pharmacological chaperones are enzyme enhancement therapy‐agents that are competitive inhibitors of the target enzyme. Each of the known β‐hexosaminidase inhibitors (low µm IC50) increased mutant enzyme levels to ≥ 10% in chronic Tay‐Sachs fibroblasts and also attenuated the thermo‐denaturation of β‐hexosaminidase. To expand the repertoire of pharmacological chaperones to more ‘drug‐like’ compounds, we screened the Maybridge library of 50 000 compounds using a real‐time assay for noncarbohydrate‐based β‐hexosaminidase inhibitors and identified several that functioned as pharmacological chaperones in patient cells. Two of these inhibitors had derivatives that had been tested in humans for other purposes. These observations lead us to screen the NINDS library of 1040 Food and Drug Administration approved compounds for pharmacological chaperones. Pyrimethamine, an antimalarial drug with well documented pharmacokinetics, was confirmed as a β‐hexosaminidase pharmacological chaperone and compared favorably with our best carbohydrate‐based pharmacological chaperone in patient cells with various mutant genotypes.

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Influence of the antipsychotic drug pipamperone on the expression of the dopamine D4 receptor

Cited by 16 publications

References 40 publications

Dopamine D₄ receptor oligomerization – contribution to receptor biogenesis

Dopamine D₄ receptor oligomerization – contribution to receptor biogenesis

Pharmacological chaperoning: A primer on mechanism and pharmacology

Lending a helping hand, screening chemical libraries for compounds that enhance β‐hexosaminidase A activity in GM2 gangliosidosis cells

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Influence of the antipsychotic drug pipamperone on the expression of the dopamine D4 receptor

Cited by 16 publications

References 40 publications

Dopamine D4 receptor oligomerization – contribution to receptor biogenesis

Dopamine D4 receptor oligomerization – contribution to receptor biogenesis

Pharmacological chaperoning: A primer on mechanism and pharmacology

Lending a helping hand, screening chemical libraries for compounds that enhance β‐hexosaminidase A activity in GM2 gangliosidosis cells

Contact Info

Product

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Dopamine D₄ receptor oligomerization – contribution to receptor biogenesis

Dopamine D₄ receptor oligomerization – contribution to receptor biogenesis