Abstract
G-protein-coupled receptors (GPCRs) are a large superfamily of plasma membrane proteins that play central roles in transducing endocrine, neural and sensory signals. In humans, more than 30 disorders are associated with mutations in GPCRs and these proteins are common drug development targets, with 30–50% of drugs targeting them. GPCR mutants are frequently misfolded, recognized as defective by the cellular quality control system, retained in the endoplasmic reticulum and do not traffic to the plasma membrane. The use of small molecules chaperones (pharmacological chaperones or “pharmacoperones”) to rescue misfolded GPCRs has provided a new approach for treatment of human diseases caused by misfolding and misrouting. This chapter provides an overview of the molecular basis of this approach using the human gonadotropin-releasing hormone receptor (hGnRHR) as model for treatment of conformational diseases provoked by misfolded GPCRs.
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Abbreviations
- ER:
-
Endoplasmic reticulum
- GnRH:
-
Gonadotropin-releasing hormone
- GPCR:
-
G-protein coupled receptors
- hGnRHR:
-
Human gonadotropin-releasing hormone receptor
- HH:
-
Hypogonadotropic hypogonadism
- HTS:
-
High throughput screening
- PM:
-
Plasma membrane
- QCS:
-
Quality control system
- tTA:
-
Tetracycline-controlled transactivator
- WT:
-
Wild-type
References
Aittomaki K, Lucena JL, Pakarinen P et al (1995) Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82:959–968
Albright JD, Reich MF, Delos Santos EG et al (1998) 5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]-[1, 4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985): an orally active arginine vasopressin antagonist with selectivity for V2 receptors. J Med Chem 41:2442–2444
Angelotti T, Daunt D, Shcherbakova OG et al (2010) Regulation of G-protein coupled receptor traffic by an evolutionary conserved hydrophobic signal. Traffic 11:560–578
Antelli A, Baldazzi L, Balsamo A et al (2006) Two novel GnRHR gene mutations in two siblings with hypogonadotropic hypogonadism. Eur J Endocrinol 155:201–205
Arakawa T, Ejima D, Kita Y et al (2006) Small molecule pharmacological chaperones: from thermodynamic stabilization to pharmaceutical drugs. Biochim Biophys Acta 1764:1677–1687
Arora KK, Chung HO, Catt KJ (1999) Influence of a species-specific extracellular amino acid on expression and function of the human gonadotropin-releasing hormone receptor. Mol Endocrinol 13:890–896
Ashton WT, Sisco RM, Kieczykowski GR et al (2001a) Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity. Bioorg Med Chem Lett 11:2597–2602
Ashton WT, Sisco RM, Yang YT et al (2001b) Substituted indole-5-carboxamides and -acetamides as potent nonpeptide GnRH receptor antagonists. Bioorg Med Chem Lett 11:1723–1726
Ashton WT, Sisco RM, Yang YT et al (2001c) Potent nonpeptide GnRH receptor antagonists derived from substituted indole-5-carboxamides and -acetamides bearing a pyridine side-chain terminus. Bioorg Med Chem Lett 11:1727–1731
Beaumont KA, Newton RA, Smit DJ et al (2005) Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk. Hum Mol Genet 14:2145–2154
Beaumont KA, Shekar SN, Newton RA et al (2007) Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles. Hum Mol Genet 16:2249–2260
Beranova M, Oliveira LM, Bedecarrats GY et al (2001) Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 86:1580–1588
Bernier V, Bichet DG, Bouvier M (2004a) Pharmacological chaperone action on G-protein-coupled receptors. Curr Opin Pharmacol 4:528–533
Bernier V, Lagace M, Bichet DG et al (2004b) Pharmacological chaperones: potential treatment for conformational diseases. Trends Endocrinol Metab 15:222–228
Bernier V, Lagace M, Lonergan M et al (2004c) Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059. Mol Endocrinol 18:2074–2084
Bernier V, Morello JP, Zarruk A et al (2006) Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 17:232–243
Bichet DG (2006) Nephrogenic diabetes insipidus. Nephrol Ther 2:387–404
Biebermann H, Schoneberg T, Krude H et al (1997) Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism. J Clin Endocrinol Metab 82:3471–3480
Blomenrohr M, Heding A, Sellar R et al (1999) Pivotal role for the cytoplasmic carboxyl-terminal tail of a nonmammalian gonadotropin-releasing hormone receptor in cell surface expression, ligand binding, and receptor phosphorylation and internalization. Mol Pharmacol 56:1229–1237
Broadley SA, Hartl FU (2009) The role of molecular chaperones in human misfolding diseases. FEBS Lett 583:2647–2653
Brooks DA (1999) Introduction: molecular chaperones of the ER: their role in protein folding and genetic disease. Semin Cell Dev Biol 10:441–442
Brothers SP, Cornea A, Janovick JA et al (2004) Human loss-of-function gonadotropin-releasing hormone receptor mutants retain wild-type receptors in the endoplasmic reticulum: molecular basis of the dominant-negative effect. Mol Endocrinol 18:1787–1797
Brothers SP, Janovick JA, Conn PM (2006) Calnexin regulated gonadotropin-releasing hormone receptor plasma membrane expression. J Mol Endocrinol 37:479–488
Brown CR, Hong-Brown LQ, Biwersi J et al (1996) Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones 1:117–125
Brown CR, Hong-Brown LQ, Welch WJ (1997a) Correcting temperature-sensitive protein folding defects. J Clin Invest 99:1432–1444
Brown CR, Hong-Brown LQ, Welch WJ (1997b) Strategies for correcting the delta F508 CFTR protein-folding defect. J Bioenerg Biomembr 29:491–502
Calebiro D, de Filippis T, Lucchi S et al (2005) Intracellular entrapment of wild-type TSH receptor by oligomerization with mutants linked to dominant TSH resistance. Hum Mol Genet 14:2991–3002
Castro-Fernandez C, Maya-Nunez G, Conn PM (2005) Beyond the signal sequence: protein routing in health and disease. Endocr Rev 26:479–503
Chaipatikul V, Erickson-Herbrandson LJ, Loh HH et al (2003) Rescuing the traffic-deficient mutants of rat mu-opioid receptors with hydrophobic ligands. Mol Pharmacol 64:32–41
Chevet E, Cameron PH, Pelletier MF et al (2001) The endoplasmic reticulum: integration of protein folding, quality control, signaling and degradation. Curr Opin Struct Biol 11:120–124
Conn PM (2010) Rescue of gonadotropin hormone receptor mutants. US7,695,917
Conn PM, Crowley WF Jr (1994) Gonadotropin-releasing hormone and its analogs. Annu Rev Med 45:391–405
Conn PM, Janovick JA (2009a) Drug development and the cellular quality control system. Trends Pharmacol Sci 30:228–233
Conn PM, Janovick JA (2009b) Trafficking and quality control of the gonadotropin releasing hormone receptor in health and disease. Mol Cell Endocrinol 299:137–145
Conn PM, Janovick JA (2011) Pharmacoperone identification for therapeutic rescue of misfolded mutant proteins. Front Endocrinol (Lausanne) 2, pii:00006
Conn PM, Ulloa-Aguirre A (2010) Trafficking of G-protein-coupled receptors to the plasma membrane: insights for pharmacoperone drugs. Trends Endocrinol Metab 21:190–197
Conn PM, Ulloa-Aguirre A (2011) Pharmacological chaperones for misfolded gonadotropin-releasing hormone receptors. Adv Pharmacol 62C:109–141
Conn PM, Rogers DC, Stewart JM et al (1982) Conversion of a gonadotropin-releasing hormone antagonist to an agonist. Nature 296:653–655
Conn PM, Janovick JA, Brothers SP et al (2006a) ‘Effective inefficiency’: cellular control of protein trafficking as a mechanism of post-translational regulation. J Endocrinol 190:13–16
Conn PM, Knollman PE, Brothers SP et al (2006b) Protein folding as posttranslational regulation: evolution of a mechanism for controlled plasma membrane expression of a G protein-coupled receptor. Mol Endocrinol 20:3035–3041
Conn PM, Ulloa-Aguirre A, Ito J et al (2007) G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol Rev 59:225–250
D’Souza-Li L, Yang B, Canaff L et al (2002) Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia. J Clin Endocrinol Metab 87:1309–1318
Dong C, Filipeanu CM, Duvernay MT et al (2007) Regulation of G protein-coupled receptor export trafficking. Biochim Biophys Acta 1768:853–870
Dou F, Netzer WJ, Tanemura K et al (2003) Chaperones increase association of tau protein with microtubules. Proc Natl Acad Sci U S A 100:721–726
Dunham JH, Hall RA (2009) Enhancement of the surface expression of G protein-coupled receptors. Trends Biotechnol 27:541–545
Estrada LD, Soto C (2006) Inhibition of protein misfolding and aggregation by small rationally-designed peptides. Curr Pharm Des 12:2557–2567
Estrada LD, Soto C (2007) Disrupting beta-amyloid aggregation for Alzheimer disease treatment. Curr Top Med Chem 7:115–126
Fan ZC, Tao YX (2009) Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese patients. J Cell Mol Med 13:3268–3282
Fan J, Perry SJ, Gao Y et al (2005a) A point mutation in the human melanin concentrating hormone receptor 1 reveals an important domain for cellular trafficking. Mol Endocrinol 19:2579–2590
Fan T, Varghese G, Nguyen T et al (2005b) A role for the distal carboxyl tails in generating the novel pharmacology and G protein activation profile of mu and delta opioid receptor hetero-oligomers. J Biol Chem 280:38478–38488
Fan J-Q, Valenzano K, Lee G, Bouvier M (2009) Pharmacological chaperones for treating obesity. US Patent application number 20090312345 (2009)
Feder ME, Hofmann GE (1999) Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annu Rev Physiol 61:243–282
Fuchs S, Amiel J, Claudel S et al (2001) Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung’s disease: evidence for selective loss of Gi coupling. Mol Med 7:115–124
Fujiwara TM, Bichet DG (2005) Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol 16:2836–2846
Gebbink MFBG, Bouma B (2010) Methods of binding of cross-beta structures by chaperones. US patent 20100015126
Gekko K, Timasheff SN (1981) Mechanism of protein stabilization by glycerol: preferential hydration in glycerol-water mixtures. Biochemistry 20:4667–4676
Gorbatyuk MS, Knox T, LaVail MM et al (2010) Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78. Proc Natl Acad Sci U S A 107:5961–5966
Granell S, Mohammad S, Ramanagoudr-Bhojappa R et al (2010) Obesity-linked variants of melanocortin-4 receptor are misfolded in the endoplasmic reticulum and can be rescued to the cell surface by a chemical chaperone. Mol Endocrinol 24:1805–1821
Gromoll J, Schulz A, Borta H et al (2002) Homozygous mutation within the conserved Ala-Phe-Asn-Glu-Thr motif of exon 7 of the LH receptor causes male pseudohermaphroditism. Eur J Endocrinol 147:597–608
Hammarstrom P, Wiseman RL, Powers ET et al (2003) Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299:713–716
Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858
Hartl FU, Hayer-Hartl M (2009) Converging concepts of protein folding in vitro and in vivo. Nat Struct Mol Biol 16:574–581
Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475:324–332
Hawtin SR (2006) Pharmacological chaperone activity of SR49059 to functionally recover misfolded mutations of the vasopressin V1a receptor. J Biol Chem 281:14604–14614
Heding A, Vrecl M, Bogerd J et al (1998) Gonadotropin-releasing hormone receptors with intracellular carboxyl-terminal tails undergo acute desensitization of total inositol phosphate production and exhibit accelerated internalization kinetics. J Biol Chem 273:11472–11477
Helenius A, Trombetta E, Hebert D, Simons JF (1997) Calnexin, calreticulin and the folding glycoproteins. Trends Biochem Sci 7:193–200
Hermosilla R, Oueslati M, Donalies U et al (2004) Disease-causing V(2) vasopressin receptors are retained in different compartments of the early secretory pathway. Traffic 5:993–1005
Huang Y, Breitwieser GE (2007) Rescue of calcium-sensing receptor mutants by allosteric modulators reveals a conformational checkpoint in receptor biogenesis. J Biol Chem 282:9517–9525
Hutt DM, Powers ET, Balch WE (2009) The proteostasis boundary in misfolding diseases of membrane traffic. FEBS Lett 583:2639–2646
Ishii S, Yoshioka H, Mannen K et al (2004) Transgenic mouse expressing human mutant alpha-galactosidase A in an endogenous enzyme deficient background: a biochemical animal model for studying active-site specific chaperone therapy for Fabry disease. Biochim Biophys Acta 1690:250–257
Ishii S, Chang HH, Kawasaki K et al (2007) Mutant alpha-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. Biochem J 406:285–295
Janovick JA, Conn PM (2010) Salt bridge integrates GPCR activation with protein trafficking. Proc Natl Acad Sci U S A 107:4454–4458
Janovick JA, Maya-Nunez G, Conn PM (2002) Rescue of hypogonadotropic hypogonadism-causing and manufactured GnRH receptor mutants by a specific protein-folding template: misrouted proteins as a novel disease etiology and therapeutic target. J Clin Endocrinol Metab 87:3255–3262
Janovick JA, Goulet M, Bush E et al (2003a) Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor. J Pharmacol Exp Ther 305:608–614
Janovick JA, Ulloa-Aguirre A, Conn PM (2003b) Evolved regulation of gonadotropin-releasing hormone receptor cell surface expression. Endocrine 22:317–327
Janovick JA, Knollman PE, Brothers SP et al (2006) Regulation of G protein-coupled receptor trafficking by inefficient plasma membrane expression: molecular basis of an evolved strategy. J Biol Chem 281:8417–8425
Janovick JA, Brothers SP, Cornea A et al (2007) Refolding of misfolded mutant GPCR: post-translational pharmacoperone action in vitro. Mol Cell Endocrinol 272:77–85
Janovick JA, Maya-Nunez G, Ulloa-Aguirre A et al (2009a) Increased plasma membrane expression of human follicle-stimulating hormone receptor by a small molecule thienopyr(im)idine. Mol Cell Endocrinol 298:84–88
Janovick JA, Patny A, Mosley R et al (2009b) Molecular mechanism of action of pharmacoperone rescue of misrouted GPCR mutants: the GnRH receptor. Mol Endocrinol 23:157–168
Janovick JA, Park BS, Conn PM (2011) Therapeutic rescue of misfolded mutants: validation of primary high throughput screens for identification of pharmacoperone drugs. PLoS One 6:e22784
Jardon-Valadez E, Ulloa-Aguirre A, Pineiro A (2008) Modeling and molecular dynamics simulation of the human gonadotropin-releasing hormone receptor in a lipid bilayer. J Phys Chem B 112:10704–10713
Jardon-Valadez E, Aguilar-Rojas A, Maya-Nunez G et al (2009) Conformational effects of Lys191 in the human GnRH receptor: mutagenesis and molecular dynamics simulations studies. J Endocrinol 201:297–307
Katada S, Tanaka M, Touhara K (2004) Structural determinants for membrane trafficking and G protein selectivity of a mouse olfactory receptor. J Neurochem 90:1453–1463
Kato A, Touhara K (2009) Mammalian olfactory receptors: pharmacology, G protein coupling and desensitization. Cell Mol Life Sci 66:3743–3753
Klausner RD, Sitia R (1990) Protein degradation in the endoplasmic reticulum. Cell 62:611–614
Klucken J, Shin Y, Masliah E et al (2004) Hsp70 reduces alpha-synuclein aggregation and toxicity. J Biol Chem 279:25497–25502
Knollman PE, Conn PM (2008) Multiple G proteins compete for binding with the human gonadotropin releasing hormone receptor. Arch Biochem Biophys 477:92–97
Knollman PE, Janovick JA, Brothers SP et al (2005) Parallel regulation of membrane trafficking and dominant-negative effects by misrouted gonadotropin-releasing hormone receptor mutants. J Biol Chem 280:24506–24514
Kobilka BK (2007) G protein coupled receptor structure and activation. Biochim Biophys Acta 1768:794–807
Kobilka BK, Deupi X (2007) Conformational complexity of G-protein-coupled receptors. Trends Pharmacol Sci 28:397–406
Krautwurst D, Yau KW, Reed RR (1998) Identification of ligands for olfactory receptors by functional expression of a receptor library. Cell 95:917–926
Krebs MP, Holden DC, Joshi P et al (2010) Molecular mechanisms of rhodopsin retinitis pigmentosa and the efficacy of pharmacological rescue. J Mol Biol 395:1063–1078
Krestel HE, Mayford M, Seeburg PH et al (2001) A GFP-equipped bidirectional expression module well suited for monitoring tetracycline-regulated gene expression in mouse. Nucleic Acids Res 29:E39
Kumar P, Ambasta RK, Veereshwarayya V et al (2007) CHIP and HSPs interact with beta-APP in a proteasome-dependent manner and influence abeta metabolism. Hum Mol Genet 16:848–864
Lagerstrom MC, Schioth HB (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 7:339–357
Le Gouill C, Parent JL, Caron CA et al (1999) Selective modulation of wild type receptor functions by mutants of G-protein-coupled receptors. J Biol Chem 274:12548–12554
Leanos-Miranda A, Janovick JA, Conn PM (2002) Receptor-misrouting: an unexpectedly prevalent and rescuable etiology in gonadotropin-releasing hormone receptor-mediated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 87:4825–4828
Leanos-Miranda A, Ulloa-Aguirre A, Ji TH et al (2003) Dominant-negative action of disease-causing gonadotropin-releasing hormone receptor (GnRHR) mutants: a trait that potentially coevolved with decreased plasma membrane expression of GnRHR in humans. J Clin Endocrinol Metab 88:3360–3367
Leanos-Miranda A, Ulloa-Aguirre A, Janovick JA et al (2005) In vitro coexpression and pharmacological rescue of mutant gonadotropin-releasing hormone receptors causing hypogonadotropic hypogonadism in humans expressing compound heterozygous alleles. J Clin Endocrinol Metab 90:3001–3008
Li T, Sandberg MA, Pawlyk BS et al (1998) Effect of vitamin A supplementation on rhodopsin mutants threonine-17 → methionine and proline-347 → serine in transgenic mice and in cell cultures. Proc Natl Acad Sci U S A 95:11933–11938
Lievremont JP, Rizzuto R, Hendershot L et al (1997) BiP, a major chaperone protein of the endoplasmic reticulum lumen, plays a direct and important role in the storage of the rapidly exchanging pool of Ca2+. J Biol Chem 272:30873–30879
Lim S, Pnueli L, Tan JH et al (2009) Negative feedback governs gonadotrope frequency-decoding of gonadotropin releasing hormone pulse-frequency. PLoS One 4:e7244
Lin X, Janovick JA, Brothers S et al (1998) Addition of catfish gonadotropin-releasing hormone (GnRH) receptor intracellular carboxyl-terminal tail to rat GnRH receptor alters receptor expression and regulation. Mol Endocrinol 12:161–171
Loo TW, Clarke DM (2007) Chemical and pharmacological chaperones as new therapeutic agents. Expert Rev Mol Med 9:1–18
Lu M, Echeverri F, Moyer BD (2003) Endoplasmic reticulum retention, degradation, and aggregation of olfactory G-protein coupled receptors. Traffic 4:416–433
Magrane J, Smith RC, Walsh K et al (2004) Heat shock protein 70 participates in the neuroprotective response to intracellularly expressed beta-amyloid in neurons. J Neurosci 24:1700–1706
Martens JW, Lumbroso S, Verhoef-Post M et al (2002) Mutant luteinizing hormone receptors in a compound heterozygous patient with complete leydig cell hypoplasia: abnormal processing causes signaling deficiency. J Clin Endocrinol Metab 87:2506–2513
Maya-Nunez G, Janovick JA, Conn PM (2000) Combined modification of intracellular and extracellular loci on human gonadotropin-releasing hormone receptor provides a mechanism for enhanced expression. Endocrine 13:401–407
Maya-Nunez G, Janovick JA, Ulloa-Aguirre A et al (2002) Molecular basis of hypogonadotropic hypogonadism: restoration of mutant (E(90)K) GnRH receptor function by a deletion at a distant site. J Clin Endocrinol Metab 87:2144–2149
Maya-Nunez G, Janovick JA, Aguilar-Rojas A et al (2011) Biochemical mechanism of pathogenesis of human gonadotropin-releasing hormone receptor mutants Thr104Ile and Tyr108Cys associated with familial hypogonadotropic hypogonadism. Mol Cell Endocrinol 337:16–23
McArdle CA, Davidson JS, Willars GB (1999) The tail of the gonadotrophin-releasing hormone receptor: desensitization at, and distal to, G protein-coupled receptors. Mol Cell Endocrinol 151:129–136
Mendes HF, van der Spuy J, Chapple JP et al (2005) Mechanisms of cell death in rhodopsin retinitis pigmentosa: implications for therapy. Trends Mol Med 11:177–185
Millar RP (2003) GnRH II and type II GnRH receptors. Trends Endocrinol Metab 14:35–43
Millar RP, Lu ZL, Pawson AJ et al (2004) Gonadotropin-releasing hormone receptors. Endocr Rev 25:235–275
Millar RP, Pawson AJ, Morgan K et al (2008) Diversity of actions of GnRHs mediated by ligand-induced selective signaling. Front Neuroendocrinol 29:17–35
Morello JP, Petaja-Repo UE, Bichet DG et al (2000a) Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci 21:466–469
Morello JP, Salahpour A, Laperriere A et al (2000b) Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 105:887–895
Morello JP, Salahpour A, Petaja-Repo UE et al (2001) Association of calnexin with wild type and mutant AVPR2 that causes nephrogenic diabetes insipidus. Biochemistry 40:6766–6775
Nakamura M, Yasuda D, Hirota N et al (2010) Specific ligands as pharmacological chaperones: the transport of misfolded G-protein coupled receptors to the cell surface. IUBMB Life 62:453–459
Naor Z (2009) Signaling by G-protein-coupled receptor (GPCR): studies on the GnRH receptor. Front Neuroendocrinol 30:10–29
Newton CL, Whay AM, McArdle CA et al (2011) Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist. Proc Natl Acad Sci U S A 108:7172–7176
Noorwez SM, Kuksa V, Imanishi Y et al (2003) Pharmacological chaperone-mediated in vivo folding and stabilization of the P23H-opsin mutant associated with autosomal dominant retinitis pigmentosa. J Biol Chem 278:14442–14450
Noorwez SM, Malhotra R, McDowell JH et al (2004) Retinoids assist the cellular folding of the autosomal dominant retinitis pigmentosa opsin mutant P23H. J Biol Chem 279:16278–16284
Noorwez SM, Ostrov DA, McDowell JH et al (2008) A high-throughput screening method for small-molecule pharmacologic chaperones of misfolded rhodopsin. Invest Ophthalmol Vis Sci 49:3224–3230
Nowak RJ, Cuny GD, Choi S et al (2010) Improving binding specificity of pharmacological chaperones that target mutant superoxide dismutase-1 linked to familial amyotrophic lateral sclerosis using computational methods. J Med Chem 53:2709–2718
Ostrov DA, Kaushai S, Noorwez SM (2009) Opsin stabilizing compounds and methods of use. US Patent application number 20090286808 (2009)
Oueslati M, Hermosilla R, Schonenberger E et al (2007) Rescue of a nephrogenic diabetes insipidus-causing vasopressin V2 receptor mutant by cell-penetrating peptides. J Biol Chem 282:20676–20685
Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5:993–996
Petaja-Repo UE, Hogue M, Laperriere A et al (2001) Newly synthesized human delta opioid receptors retained in the endoplasmic reticulum are retrotranslocated to the cytosol, deglycosylated, ubiquitinated, and degraded by the proteasome. J Biol Chem 276:4416–4423
Petaja-Repo UE, Hogue M, Bhalla S et al (2002) Ligands act as pharmacological chaperones and increase the efficiency of delta opioid receptor maturation. EMBO J 21:1628–1637
Rambold AS, Miesbauer M, Rapaport D et al (2006) Association of Bcl-2 with misfolded prion protein is linked to the toxic potential of cytosolic PrP. Mol Biol Cell 17:3356–3368
Rana S, Besson G, Cook DG et al (1997) Role of CCR5 in infection of primary macrophages and lymphocytes by macrophage-tropic strains of human immunodeficiency virus: resistance to patient-derived and prototype isolates resulting from the delta ccr5 mutation. J Virol 71:3219–3227
Rannikko A, Pakarinen P, Manna PR et al (2002) Functional characterization of the human FSH receptor with an inactivating Ala189Val mutation. Mol Hum Reprod 8:311–317
Ravindran RK, Tablin F, Crowe JH et al (2005) Resistance to dehydration damage in HeLa cells correlates with the presence of endogenous heat shock proteins. Cell Preserv Technol 3:155–164
Re M, Pampillo M, Savard M et al (2010) The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane. PLoS One 5:e11489
Robben JH, Deen PM (2007) Pharmacological chaperones in nephrogenic diabetes insipidus: possibilities for clinical application. BioDrugs 21:157–166
Robben JH, Sze M, Knoers NV et al (2006) Rescue of vasopressin V2 receptor mutants by chemical chaperones: specificity and mechanism. Mol Biol Cell 17:379–386
Robben JH, Sze M, Knoers NV et al (2007) Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 292:F253–F260
Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529
Saliba RS, Munro PM, Luthert PJ et al (2002) The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation. J Cell Sci 115:2907–2918
Sampedro JG, Uribe S (2004) Trehalose-enzyme interactions result in structure stabilization and activity inhibition. The role of viscosity. Mol Cell Biochem 256–257:319–327
Sasaki S, Cho N, Nara Y et al (2003) Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor. J Med Chem 46:113–124
Schlyer S, Horuk R (2006) I want a new drug: G-protein-coupled receptors in drug development. Drug Discov Today 11:481–493
Schubert U, Anton LC, Gibbs J et al (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774
Schulein R, Zuhlke K, Krause G et al (2001) Functional rescue of the nephrogenic diabetes insipidus-causing vasopressin V2 receptor mutants G185C and R202C by a second site suppressor mutation. J Biol Chem 276:8384–8392
Serradeil-Le Gal C, Lacour C, Valette G et al (1996) Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist. J Clin Invest 98:2729–2738
Shimura H, Schwartz D, Gygi SP et al (2004) CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem 279:4869–4876
Sigurdsson EM, Permanne B, Soto C et al (2000) In vivo reversal of amyloid-beta lesions in rat brain. J Neuropathol Exp Neurol 59:11–17
Soto C (2001) Protein misfolding and disease; protein refolding and therapy. FEBS Lett 498:204–207
Sung CH, Schneider BG, Agarwal N et al (1991) Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A 88:8840–8844
Tahara A, Tomura Y, Wada KI et al (1997) Pharmacological profile of YM087, a novel potent nonpeptide vasopressin V1A and V2 receptor antagonist, in vitro and in vivo. J Pharmacol Exp Ther 282:301–308
Tanaka H, Moroi K, Iwai J et al (1998) Novel mutations of the endothelin B receptor gene in patients with Hirschsprung’s disease and their characterization. J Biol Chem 273:11378–11383
Tao YX (2010) The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev 31:506–543
Tao YX, Segaloff DL (2003) Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. Endocrinology 144:4544–4551
Tranchant T, Durand G, Gauthier C et al (2011) Preferential beta-arrestin signalling at low receptor density revealed by functional characterization of the human FSH receptor A189 V mutation. Mol Cell Endocrinol 331:109–118
Ulloa-Aguirre A, Conn PM (2009) Targeting of G protein-coupled receptors to the plasma membrane in health and disease. Front Biosci 14:973–994
Ulloa-Aguirre A, Timossi C (2000) Biochemical and functional aspects of gonadotrophin-releasing hormone and gonadotrophins. Reprod Biomed Online 1:48–62
Ulloa-Aguirre A, Conn PM et al (1998) G protein-coupled receptors and the G protein family. In: Handbook of physiology. Oxford University Press, New York, pp 87–124, Section 7
Ulloa-Aguirre A, Janovick JA, Leanos-Miranda A et al (2003) Misrouted cell surface receptors as a novel disease aetiology and potential therapeutic target: the case of hypogonadotropic hypogonadism due to gonadotropin-releasing hormone resistance. Expert Opin Ther Targets 7:175–185
Ulloa-Aguirre A, Janovick JA, Brothers SP et al (2004a) Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease. Traffic 5:821–837
Ulloa-Aguirre A, Janovick JA, Leanos-Miranda A et al (2004b) Misrouted cell surface GnRH receptors as a disease aetiology for congenital isolated hypogonadotrophic hypogonadism. Hum Reprod Update 10:177–192
Ulloa-Aguirre A, Janovick JA, Leanos-Miranda A et al (2006) G-protein-coupled receptor trafficking: understanding the chemical basis of health and disease. ACS Chem Biol 1:631–638
Vos TJ, Caracoti A, Che JL et al (2004) Identification of 2-[2-[2-(5-bromo-2- methoxyphenyl)-ethyl]-3-fluorophenyl]-4,5-dihydro-1H-imidazole (ML00253764), a small molecule melanocortin 4 receptor antagonist that effectively reduces tumor-induced weight loss in a mouse model. J Med Chem 47:1602–1604
Werner ED, Brodsky JL, McCracken AA (1996) Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate. Proc Natl Acad Sci U S A 93:13797–13801
Wetzel CH, Oles M, Wellerdieck C et al (1999) Specificity and sensitivity of a human olfactory receptor functionally expressed in human embryonic kidney 293 cells and Xenopus Laevis oocytes. J Neurosci 19:7426–7433
Wu G, Zhao G, He Y (2003) Distinct pathways for the trafficking of angiotensin II and adrenergic receptors from the endoplasmic reticulum to the cell surface: Rab1-independent transport of a G protein-coupled receptor. J Biol Chem 278:47062–47069
Wuller S, Wiesner B, Loffler A et al (2004) Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors. J Biol Chem 279:47254–47263
Zhu X, Wess J (1998) Truncated V2 vasopressin receptors as negative regulators of wild-type V2 receptor function. Biochemistry 37:15773–15784
Acknowledgements
This work was supported by NIH grants: TW/HD-, DK-85040, OD012220, OD 011092 and HD-18185. Alfredo Ulloa-Aguirre is supported by CONACyT (Mexico) grant 86881. We thank Jo Ann Binkerd for formatting the manuscript.
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Maya-Núñez, G., Ulloa-Aguirre, A., Janovick, J.A., Conn, P.M. (2012). Pharmacological Chaperones Correct Misfolded GPCRs and Rescue Function: Protein Trafficking as a Therapeutic Target. In: Dupré, D., Hébert, T., Jockers, R. (eds) GPCR Signalling Complexes – Synthesis, Assembly, Trafficking and Specificity. Subcellular Biochemistry, vol 63. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4765-4_14
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