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Pharmacological Chaperones Correct Misfolded GPCRs and Rescue Function: Protein Trafficking as a Therapeutic Target

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Part of the book series: Subcellular Biochemistry ((SCBI,volume 63))

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.

Keywords

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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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Bernier V, Bichet DG, Bouvier M (2004a) Pharmacological chaperone action on G-protein-coupled receptors. Curr Opin Pharmacol 4:528–533

    Article  PubMed  CAS  Google Scholar 

  • Bernier V, Lagace M, Bichet DG et al (2004b) Pharmacological chaperones: potential treatment for conformational diseases. Trends Endocrinol Metab 15:222–228

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Bichet DG (2006) Nephrogenic diabetes insipidus. Nephrol Ther 2:387–404

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Broadley SA, Hartl FU (2009) The role of molecular chaperones in human misfolding diseases. FEBS Lett 583:2647–2653

    Article  PubMed  CAS  Google Scholar 

  • Brooks DA (1999) Introduction: molecular chaperones of the ER: their role in protein folding and genetic disease. Semin Cell Dev Biol 10:441–442

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Brothers SP, Janovick JA, Conn PM (2006) Calnexin regulated gonadotropin-releasing hormone receptor plasma membrane expression. J Mol Endocrinol 37:479–488

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Brown CR, Hong-Brown LQ, Welch WJ (1997a) Correcting temperature-sensitive protein folding defects. J Clin Invest 99:1432–1444

    Article  PubMed  CAS  Google Scholar 

  • Brown CR, Hong-Brown LQ, Welch WJ (1997b) Strategies for correcting the delta F508 CFTR protein-folding defect. J Bioenerg Biomembr 29:491–502

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Castro-Fernandez C, Maya-Nunez G, Conn PM (2005) Beyond the signal sequence: protein routing in health and disease. Endocr Rev 26:479–503

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Conn PM (2010) Rescue of gonadotropin hormone receptor mutants. US7,695,917

    Google Scholar 

  • Conn PM, Crowley WF Jr (1994) Gonadotropin-releasing hormone and its analogs. Annu Rev Med 45:391–405

    Article  PubMed  CAS  Google Scholar 

  • Conn PM, Janovick JA (2009a) Drug development and the cellular quality control system. Trends Pharmacol Sci 30:228–233

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Conn PM, Janovick JA (2011) Pharmacoperone identification for therapeutic rescue of misfolded mutant proteins. Front Endocrinol (Lausanne) 2, pii:00006

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Conn PM, Ulloa-Aguirre A (2011) Pharmacological chaperones for misfolded gonadotropin-releasing hormone receptors. Adv Pharmacol 62C:109–141

    Article  Google Scholar 

  • Conn PM, Rogers DC, Stewart JM et al (1982) Conversion of a gonadotropin-releasing hormone antagonist to an agonist. Nature 296:653–655

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Dong C, Filipeanu CM, Duvernay MT et al (2007) Regulation of G protein-coupled receptor export trafficking. Biochim Biophys Acta 1768:853–870

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Dunham JH, Hall RA (2009) Enhancement of the surface expression of G protein-coupled receptors. Trends Biotechnol 27:541–545

    Article  PubMed  CAS  Google Scholar 

  • Estrada LD, Soto C (2006) Inhibition of protein misfolding and aggregation by small rationally-designed peptides. Curr Pharm Des 12:2557–2567

    Article  PubMed  CAS  Google Scholar 

  • Estrada LD, Soto C (2007) Disrupting beta-amyloid aggregation for Alzheimer disease treatment. Curr Top Med Chem 7:115–126

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Fan J-Q, Valenzano K, Lee G, Bouvier M (2009) Pharmacological chaperones for treating obesity. US Patent application number 20090312345 (2009)

    Google Scholar 

  • Feder ME, Hofmann GE (1999) Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annu Rev Physiol 61:243–282

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Fujiwara TM, Bichet DG (2005) Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol 16:2836–2846

    Article  PubMed  CAS  Google Scholar 

  • Gebbink MFBG, Bouma B (2010) Methods of binding of cross-beta structures by chaperones. US patent 20100015126

    Google Scholar 

  • Gekko K, Timasheff SN (1981) Mechanism of protein stabilization by glycerol: preferential hydration in glycerol-water mixtures. Biochemistry 20:4667–4676

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Hammarstrom P, Wiseman RL, Powers ET et al (2003) Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299:713–716

    Article  PubMed  CAS  Google Scholar 

  • Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858

    Article  PubMed  CAS  Google Scholar 

  • Hartl FU, Hayer-Hartl M (2009) Converging concepts of protein folding in vitro and in vivo. Nat Struct Mol Biol 16:574–581

    Article  PubMed  CAS  Google Scholar 

  • Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475:324–332

    Article  PubMed  CAS  Google Scholar 

  • Hawtin SR (2006) Pharmacological chaperone activity of SR49059 to functionally recover misfolded mutations of the vasopressin V1a receptor. J Biol Chem 281:14604–14614

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Helenius A, Trombetta E, Hebert D, Simons JF (1997) Calnexin, calreticulin and the folding glycoproteins. Trends Biochem Sci 7:193–200

    CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Hutt DM, Powers ET, Balch WE (2009) The proteostasis boundary in misfolding diseases of membrane traffic. FEBS Lett 583:2639–2646

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Janovick JA, Conn PM (2010) Salt bridge integrates GPCR activation with protein trafficking. Proc Natl Acad Sci U S A 107:4454–4458

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Janovick JA, Ulloa-Aguirre A, Conn PM (2003b) Evolved regulation of gonadotropin-releasing hormone receptor cell surface expression. Endocrine 22:317–327

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Kato A, Touhara K (2009) Mammalian olfactory receptors: pharmacology, G protein coupling and desensitization. Cell Mol Life Sci 66:3743–3753

    Article  PubMed  CAS  Google Scholar 

  • Klausner RD, Sitia R (1990) Protein degradation in the endoplasmic reticulum. Cell 62:611–614

    Article  PubMed  CAS  Google Scholar 

  • Klucken J, Shin Y, Masliah E et al (2004) Hsp70 reduces alpha-synuclein aggregation and toxicity. J Biol Chem 279:25497–25502

    Article  PubMed  CAS  Google Scholar 

  • Knollman PE, Conn PM (2008) Multiple G proteins compete for binding with the human gonadotropin releasing hormone receptor. Arch Biochem Biophys 477:92–97

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Kobilka BK (2007) G protein coupled receptor structure and activation. Biochim Biophys Acta 1768:794–807

    Article  PubMed  CAS  Google Scholar 

  • Kobilka BK, Deupi X (2007) Conformational complexity of G-protein-coupled receptors. Trends Pharmacol Sci 28:397–406

    Article  PubMed  CAS  Google Scholar 

  • Krautwurst D, Yau KW, Reed RR (1998) Identification of ligands for olfactory receptors by functional expression of a receptor library. Cell 95:917–926

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Lagerstrom MC, Schioth HB (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 7:339–357

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Loo TW, Clarke DM (2007) Chemical and pharmacological chaperones as new therapeutic agents. Expert Rev Mol Med 9:1–18

    Article  PubMed  Google Scholar 

  • Lu M, Echeverri F, Moyer BD (2003) Endoplasmic reticulum retention, degradation, and aggregation of olfactory G-protein coupled receptors. Traffic 4:416–433

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Millar RP (2003) GnRH II and type II GnRH receptors. Trends Endocrinol Metab 14:35–43

    Article  PubMed  CAS  Google Scholar 

  • Millar RP, Lu ZL, Pawson AJ et al (2004) Gonadotropin-releasing hormone receptors. Endocr Rev 25:235–275

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Morello JP, Petaja-Repo UE, Bichet DG et al (2000a) Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci 21:466–469

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Naor Z (2009) Signaling by G-protein-coupled receptor (GPCR): studies on the GnRH receptor. Front Neuroendocrinol 30:10–29

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Ostrov DA, Kaushai S, Noorwez SM (2009) Opsin stabilizing compounds and methods of use. US Patent application number 20090286808 (2009)

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5:993–996

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Robben JH, Deen PM (2007) Pharmacological chaperones in nephrogenic diabetes insipidus: possibilities for clinical application. BioDrugs 21:157–166

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Schlyer S, Horuk R (2006) I want a new drug: G-protein-coupled receptors in drug development. Drug Discov Today 11:481–493

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Soto C (2001) Protein misfolding and disease; protein refolding and therapy. FEBS Lett 498:204–207

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Tao YX (2010) The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev 31:506–543

    Article  PubMed  CAS  Google Scholar 

  • Tao YX, Segaloff DL (2003) Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. Endocrinology 144:4544–4551

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Ulloa-Aguirre A, Timossi C (2000) Biochemical and functional aspects of gonadotrophin-releasing hormone and gonadotrophins. Reprod Biomed Online 1:48–62

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, Wess J (1998) Truncated V2 vasopressin receptors as negative regulators of wild-type V2 receptor function. Biochemistry 37:15773–15784

    Article  PubMed  CAS  Google Scholar 

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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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