Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants

Morello, Jean-Pierre; Salahpour, Ali; Laperrière, André; Bernier, Virginie; Arthus, Marie‐Françoise; Lonergan, Michèle; Petäjä-Repo, Ulla E.; Angers, Stéphane; Morin, Denis; Bichet, Daniel G.; Bouvier, Michel

doi:10.1172/jci8688

Cited by 518 publications

(383 citation statements)

References 35 publications

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“…The present study is a needed antecedent to selection of the appropriate time for pulsatile administration of pharmacoperones in vivo and suggests that, at least in the case of GnRH receptor mutants with three chemical classes of pharmacoperones, the drug need not be present at the time of synthesis, as appears to be the case for other vasopressin receptor subtypes (Hawtin, 2006;Morello et al, 2000;Wuller et al, 2004). The present model suggests that pharmacoperones act post-translationally to aid in receptor folding.…”

Section: Discussionmentioning

confidence: 88%

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Janovick

Brothers

Cornea

et al. 2007

Molecular and Cellular Endocrinology

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SUMMARYAll reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct mis-folding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.

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Section: Discussionmentioning

confidence: 88%

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Janovick

Brothers

Cornea

et al. 2007

Molecular and Cellular Endocrinology

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“…Furthermore, the total amount of CB1-EGFP fluorescence in cells does not change notably along the time courses studied. The alternative hypothesis of immature receptors being translocated from the ER to the plasma membrane by a chaperone effect of membrane-permeant inverse agonists, as shown for mutant vasopressin V2 receptors (41) or ␦ opioid receptors (50), seems also not applicable here; intracellular CB1Rs are not localized in the ER and are of endocytic origin. Furthermore, AM281-induced externalization depends on Rab4 and is blocked by monensin, showing involvement of recycling pathways.…”

Section: Cb1r Is Constitutively Endocytosed and Am281-induced Externamentioning

confidence: 84%

“…Intuitively, CB1R-containing intracellular vesicles could correspond to maturing receptors in the neosynthetic pathway. In fact, several constitutively active GPCRs, like mutants of the vasopressin V2 receptor (41) or the wild type ␦-opioid receptor (42), are retained in the ER before reaching the cell surface, leading to a mostly intracellular phenotype. However, we found no effect of protein synthesis inhibition by cycloheximide (up to 4 h) on the intracellular distribution of CB1-EGFP.…”

Section: Cb1r Is Constitutively Endocytosed and Am281-induced Externamentioning

confidence: 99%

Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor

Leterrier

Bonnard

Carrel

et al. 2004

Journal of Biological Chemistry

216

234

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The CB1 cannabinoid receptor (CB1R) displays a significant level of ligand-independent (i.e. constitutive) activity, either when heterologously expressed in nonneuronal cells or in neurons where CB1Rs are endogenous. The present study investigates the consequences of constitutive activity on the intracellular trafficking of CB1R. When transfected in HEK-293 cells, CB1R is present at the plasma membrane, but a substantial proportion (ϳ85%) of receptors is localized in intracellular vesicles. Detailed analysis of CB1-EGFP expressed in HEK-293 cells shows that the intracellular CB1R population is mostly of endocytic origin and that treatment with inverse agonist AM281 traps CB1R at the plasma membrane through a monensin-sensitive recycling pathway. Co-transfection with dominant positive or dominant negative mutants of the small GTPases Rab5 and Rab4, but not Rab11, profoundly modifies the steady-state and ligand-induced intracellular distribution of CB1R, indicating that constitutive endocytosis is Rab5-dependent, whereas constitutive recycling is mediated by Rab4. In conclusion, our results indicate that, due to its natural constitutive activity, CB1R permanently and constitutively cycles between plasma membrane and endosomes, leading to a predominantly intracellular localization at steady state.

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“…14 and 15). A variety of mutations in the V2R resulting in abnormal ligand binding, G protein coupling, and receptor trafficking have been associated with NDI (16)(17)(18). One of the first-characterized naturally occurring mutations of the V2R associated with NDI was a substitution of arginine 137 by histidine, V2R(R137H) (14,(18)(19)(20).…”

mentioning

confidence: 99%

Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus

Barak¹

2000

Proceedings of the National Academy of Sciences

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Agonist-dependent desensitization and internalization of G proteincoupled receptors (GPCR) are mediated by the binding of arrestins to phosphorylated receptors. The affinity of arrestins for the phosphorylated GPCR regulates the ability of the internalized receptor to be dephosphorylated and recycled back to the plasma membrane. In this study, we show that the naturally occurring loss of function vasopressin receptor mutation R137H, which is associated with familial nephrogenic diabetes insipidus, induces constitutive arrestinmediated desensitization. In contrast to the wild-type vasopressin receptor, the nonsignaling R137H receptor is phosphorylated and sequestered in arrestin-associated intracellular vesicles even in the absence of agonist. Eliminating molecular determinants on the receptor that promote high affinity arrestin-receptor interaction reestablishes plasma membrane localization and the ability of the mutated receptors to signal. These findings suggest that unregulated desensitization can contribute to the etiology of a GPCR-based disease, implying that pharmacological targeting of GPCR desensitization may be therapeutically beneficial.

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Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants

Cited by 518 publications

References 35 publications

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor

Constitutive arrestin-mediated desensitization of a human vasopressin receptor mutant associated with nephrogenic diabetes insipidus

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