Abstract
Pharmacological chaperones (PCs) are small molecules that bind to nascent protein targets to facilitate their biogenesis. The ability of PCs to assist in the folding and subsequent forward trafficking of disease-causative protein misfolding mutants has opened new avenues for the treatment of conformational diseases such as cystic fibrosis and lysosomal storage disorders. In this chapter, an overview of the use of PCs for the treatment of conformational disorders is provided. Beyond the therapeutic application of PCs for the treatment of these disorders, pharmacological chaperoning of wild-type integral membrane proteins is discussed. Central to this discussion is the notion that the endoplasmic reticulum is a reservoir of viable but inefficiently processed wild-type protein folding intermediates whose biogenesis can be facilitated by PCs to increase functional pools. To date, the potential therapeutic use of PCs to enhance the biogenesis of wild-type proteins has received little attention. Here the rationale for the development of PCs that target WT proteins is discussed. Also considered is the likelihood that some commonly used therapeutic agents may exert unrecognized pharmacological chaperoning activity on wild-type targets in patient populations.
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References
Araki K, Nagata K (2011) Protein folding and quality control in the ER. Cold Spring Harb Perspect Biol 3:a007526
Beerepoot P, Lam VM, Salahpour A (2016) Pharmacological chaperones of the dopamine transporter rescue dopamine transporter deficiency syndrome mutations in heterologous cells. J Biol Chem 291:22053–22062
Beerepoot P, Nazari R, Salahpour A (2017) Pharmacological chaperone approaches for rescuing GPCR mutants: current state, challenges, and screening strategies. Pharmacol Res 117:242–251
Bernier V, Morello JP, Zarruk A, Debrand N, Salahpour A, Lonergan M, Arthus MF, Laperriere A, Brouard R, Bouvier M, Bichet DG (2006) Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 17:232–243
Boyd R, Lee G, Rybczynski P, Benjamin E, Khanna R, Wustman B, Valenzano K (2013) Pharmacological chaperones as therapeutics for lysosomal storage diseases. J Med Chem 56:2705–2725
Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, Huang X, Waltz D, Patel NR, Rodman D, VX09-809-102 Study Group (2014) A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med 2:527–538
Breitwieser GE (2013) The calcium sensing receptor life cycle: trafficking, cell surface expression, and degradation. Best Pract Res Clin Endocrinol Metab 27:303–313
Breitwieser GE (2014) Pharmacoperones and the calcium sensing receptor: exogenous and endogenous regulators. Pharmacol Res 83:30–37
Brothers SP, Cornea A, Janovick JA, Conn PM (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
Calvo AC, Scherer T, Pey AL, Ying M, Winge I, McKinney J, Haavik J, Thony B, Martinez A (2010) Effect of pharmacological chaperones on brain tyrosine hydroxylase and tryptophan hydroxylase 2. J Neurochem 114:853–863
Canals M, Lopez-Gimenez JF, Milligan G (2009) Cell surface delivery and structural re-organization by pharmacological chaperones of an oligomerization-defective alpha(1b)-adrenoceptor mutant demonstrates membrane targeting of GPCR oligomers. Biochem J 417:161–172
Cavanaugh A, McKenna J, Stepanchick A, Breitwieser GE (2010a) Calcium-sensing receptor biosynthesis includes a cotranslational conformational checkpoint and endoplasmic reticulum retention. J Biol Chem 285:19854–19864
Cavanaugh A, McKenna J, Stepanchick A, Breitwieser GE (2010b) Calcium-sensing receptor biosynthesis includes a cotranslational conformational checkpoint and endoplasmic reticulum retention. J Biol Chem 285:19854–19864
Celej MS, Montich GG, Fidelio GD (2003) Protein stability induced by ligand binding correlates with changes in protein flexibility. Protein Sci 12:1496–1506
Chaipatikul V, Erickson-Herbrandson LJ, Loh HH, Law PY (2003) Rescuing the traffic-deficient mutants of rat mu-opioid receptors with hydrophobic ligands. Mol Pharmacol 64:32–41
Chen PC, Olson EM, Zhou Q, Kryukova Y, Sampson HM, Thomas DY, Shyng SL (2013) Carbamazepine as a novel small molecule corrector of trafficking-impaired ATP-sensitive potassium channels identified in congenital hyperinsulinism. J Biol Chem 288:20942–20954
Chen Y, Liu-Chen LY (2009) Chaperone-like effects of cell-permeant ligands on opioid receptors. Front Biosci 14:634–643
Christianson JC, Green WN (2004) Regulation of nicotinic receptor expression by the ubiquitin-proteasome system. EMBO J 23:4156–4165
Citro V, Pena-Garcia J, den-Haan H, Perez-Sanchez H, Del Prete R, Liguori L, Cimmaruta C, Lukas J, Cubellis MV, Andreotti G (2016) Identification of an allosteric binding site on human lysosomal alpha-galactosidase opens the way to new pharmacological chaperones for Fabry disease. PLoS One 11:e0165463
Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS, Ashlock MA, Ballmann M, Boyle MP, Bronsveld I, Campbell PW et al (2012) Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 67:12–18
Clark NE, Metcalf MC, Best D, Fleet GW, Garman SC (2012) Pharmacological chaperones for human α-N-acetylgalactosaminidase. Proc Natl Acad Sci U S A 109:17400–17405
Coleman SK, Moykkynen T, Hinkkuri S, Vaahtera L, Korpi ER, Pentikainen OT, Keinanen K (2010) Ligand-binding domain determines endoplasmic reticulum exit of AMPA receptors. J Biol Chem 285:36032–36039
Coleman SK, Moykkynen T, Jouppila A, Koskelainen S, Rivera C, Korpi ER, Keinanen K (2009) Agonist occupancy is essential for forward trafficking of AMPA receptors. J Neurosci 29:303–312
Conn P, Janovick J, Brothers S, Knollman P (2006) “Effective inefficiency”: cellular control of protein trafficking as a mechanism of post-translational regulation. J Endocrinol 190:13–16
Conn PM, Janovick JA (2009) 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(6). pii: 00006. PMID: 21633718
Conn PM, Smith E, Hodder P, Janovick JA, Smithson DC (2013) High-throughput screen for pharmacoperones of the vasopressin type 2 receptor. J Biomol Screen 18:930–937
Conn PM, Smithson DC, Hodder PS, Stewart MD, Behringer RR, Smith E, Ulloa-Aguirre A, Janovick JA (2014) Transitioning pharmacoperones to therapeutic use: in vivo proof-of-principle and design of high throughput screens. Pharmacol Res 83:38–51
Conn PM, Spicer TP, Scampavia L, Janovick JA (2015) Assay strategies for identification of therapeutic leads that target protein trafficking. Trends Pharmacol Sci 36:498–505
Conn PM, Ulloa-Aguirre A (2011) Pharmacological chaperones for misfolded gonadotropin-releasing hormone receptors. Adv Pharmacol 62:109–141
Corringer PJ, Sallette J, Changeux JP (2006) Nicotine enhances intracellular nicotinic receptor maturation: a novel mechanism of neural plasticity? J Physiol Paris 99:162–171
Dennis AT, Wang L, Wan H, Nassal D, Deschenes I, Ficker E (2012) Molecular determinants of pentamidine-induced hERG trafficking inhibition. Mol Pharmacol 81:198–209
Devaraneni PK, Martin GM, Olson EM, Zhou Q, Shyng SL (2015) Structurally distinct ligands rescue biogenesis defects of the KATP channel complex via a converging mechanism. J Biol Chem 290:7980–7991
Du K, Lukacs GL (2009) Cooperative assembly and misfolding of CFTR domains in vivo. Mol Biol Cell 20:1903–1915
Du K, Sharma M, Lukacs GL (2005) The DeltaF508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR. Nat Struct Mol Biol 12:17–25
Eshaq RS, Stahl LD, Stone R 2nd, Smith SS, Robinson LC, Leidenheimer NJ (2010) GABA acts as a ligand chaperone in the early secretory pathway to promote cell surface expression of GABAA receptors. Brain Res 1346:1–13
Fan J, Perry SJ, Gao Y, Schwarz DA, Maki RA (2005) A point mutation in the human melanin concentrating hormone receptor 1 reveals an important domain for cellular trafficking. Mol Endocrinol 19:2579–2590
Fleck MW (2006) Glutamate receptors and endoplasmic reticulum quality control: looking beneath the surface. Neuroscientist 12:232–244
Galietta LJ (2013) Managing the underlying cause of cystic fibrosis: a future role for potentiators and correctors. Paediatr Drugs 15(5):393–402. https://doi.org/10.1007/s40272-013-0035-3
Garman SC, Garboczi DN (2004) The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. J Mol Biol 337:319–335
Generoso SF, Giustiniano M, La Regina G, Bottone S, Passacantilli S, Di Maro S, Cassese H, Bruno A, Mallardo M, Dentice M et al (2015) Pharmacological folding chaperones act as allosteric ligands of Frizzled4. Nat Chem Biol 11:280–286
Germain DP, Fan JQ (2009) Pharmacological chaperone therapy by active-site-specific chaperones in Fabry disease: in vitro and preclinical studies. Int J Clin Pharmacol Ther 47(Suppl 1):S111–S117
Germain DP, Giugliani R, Hughes DA, Mehta A, Nicholls K, Barisoni L, Jennette CJ, Bragat A, Castelli J, Sitaraman S et al (2012) Safety and pharmacodynamic effects of a pharmacological chaperone on alpha-galactosidase a activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies. Orphanet J Rare Dis 7:91
Gersting SW, Lagler FB, Eichinger A, Kemter KF, Danecka MK, Messing DD, Staudigl M, Domdey KA, Zsifkovits C, Fingerhut R et al (2010) Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo. Hum Mol Genet 19:2039–2049
Gill MB, Vivithanaporn P, Swanson GT (2009) Glutamate binding and conformational flexibility of ligand-binding domains are critical early determinants of efficient kainate receptor biogenesis. J Biol Chem 284:14503–14512
Giugliani R, Waldek S, Germain DP, Nicholls K, Bichet DG, Simosky JK, Bragat AC, Castelli JP, Benjamin ER, Boudes PF (2013) A phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamic effects. Mol Genet Metab 109:86–92
Gong Q, Jones MA, Zhou Z (2006) Mechanisms of pharmacological rescue of trafficking-defective hERG mutant channels in human long QT syndrome. J Biol Chem 281:4069–4074
Gorrie GH, Vallis Y, Stephenson A, Whitfield J, Browning B, Smart TG, Moss SJ (1997) Assembly of GABAA receptors composed of alpha1 and beta2 subunits in both cultured neurons and fibroblasts. J Neurosci 17:6587–6596
Guce AI, Clark NE, Rogich JJ, Garman SC (2011) The molecular basis of pharmacological chaperoning in human α-galactosidase. Chem Biol 18:1521–1526
Hanrahan J, Sampson H, Thomas D (2013) Novel pharmacological strategies to treat cystic fibrosis. Trends Pharmacol Sci 34:119–125
Hay Mele B, Citro V, Andreotti G, Cubellis MV (2015) Drug repositioning can accelerate discovery of pharmacological chaperones. Orphanet J Rare Dis 10:55
Hole M, Underhaug J, Diez H, Ying M, Rohr AK, Jorge-Finnigan A, Fernandez-Castillo N, Garcia-Cazorla A, Andersson KK, Teigen K, Martinez A (2015) Discovery of compounds that protect tyrosine hydroxylase activity through different mechanisms. Biochim Biophys Acta 1854:1078–1089
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
Hubner CA, Jentsch TJ (2002) Ion channel diseases. Hum Mol Genet 11:2435–2445
Hughes DA, Nicholls K, Shankar SP, Sunder-Plassmann G, Koeller D, Nedd K, Vockley G, Hamazaki T, Lachmann R, Ohashi T et al (2017) Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J Med Genet 54:288–296
Janovick J, Maya-Nunez G, Conn P (2002a) 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, Maya-Nunez G, Conn PM (2002b) 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, Maya-Nunez G, Ulloa-Aguirre A, Huhtaniemi IT, Dias JA, Verbost P, Conn PM (2009) 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, 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
Janovick JA, Stewart MD, Jacob D, Martin LD, Deng JM, Stewart CA, Wang Y, Cornea A, Chavali L, Lopez S et al (2013) Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy. Proc Natl Acad Sci U S A 110:21030–21035
Jean-Alphonse F, Perkovska S, Frantz MC, Durroux T, Mejean C, Morin D, Loison S, Bonnet D, Hibert M, Mouillac B, Mendre C (2009) Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 20:2190–2203
Kenny AV, Cousins SL, Pinho L, Stephenson FA (2009) The integrity of the glycine co-agonist binding site of N-methyl-D-aspartate receptors is a functional quality control checkpoint for cell surface delivery. J Biol Chem 284:324–333
Knollman PE, Janovick JA, Brothers SP, Conn PM (2005) Parallel regulation of membrane trafficking and dominant-negative effects by misrouted gonadotropin-releasing hormone receptor mutants. J Biol Chem 280:24506–24514
Kobayashi H, Ogawa K, Yao R, Lichtarge O, Bouvier M (2009) Functional rescue of beta-adrenoceptor dimerization and trafficking by pharmacological chaperones. Traffic 10:1019–1033
Kuryatov A, Luo J, Cooper J, Lindstrom J (2005) Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors. Mol Pharmacol 68:1839–1851
Kuryatov A, Mukherjee J, Lindstrom J (2013) Chemical chaperones exceed the chaperone effects of RIC-3 in promoting assembly of functional alpha7 AChRs. PLoS One 8:e62246
Kusek J, Yang Q, Witek M, Gruber CW, Nanoff C, Freissmuth M (2015) Chaperoning of the A1-adenosine receptor by endogenous adenosine – an extension of the retaliatory metabolite concept. Mol Pharmacol 87:39–51
Labrecque P, Roy SJ, Frechette L, Iorio-Morin C, Gallant MA, Parent JL (2013) Inverse agonist and pharmacochaperone properties of MK-0524 on the prostanoid DP1 receptor. PLoS One 8:e65767
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, Janovick JA, Conn PM (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
Leidenheimer NJ (2017) Cognate ligand chaperoning: a novel mechanism for the post-translational regulation of neurotransmitter receptor biogenesis. Front Cell Neurosci 11:245
Leidenheimer NJ, Ryder KG (2014) Pharmacological chaperoning: a primer on mechanism and pharmacology. Pharmacol Res 83:10–19
Leskela TT, Lackman JJ, Vierimaa MM, Kobayashi H, Bouvier M, Petaja-Repo UE (2012) Cys-27 variant of human delta-opioid receptor modulates maturation and cell surface delivery of Phe-27 variant via heteromerization. J Biol Chem 287:5008–5020
Lester HA, Xiao C, Srinivasan R, Son CD, Miwa J, Pantoja R, Banghart MR, Dougherty DA, Goate AM, Wang JC (2009) Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery. AAPS J 11:167–177
Lieberman RL, Wustman BA, Huertas P, Powe AC Jr, Pine CW, Khanna R, Schlossmacher MG, Ringe D, Petsko GA (2007) Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease. Nat Chem Biol 3:101–107
Lindquist SL, Kelly JW (2011) Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases: progress and prognosis. Cold Spring Harb Perspect Biol 3(12). pii: a004507. doi: https://doi.org/10.1101/cshperspect.a004507
Loo TW, Bartlett MC, Clarke DM (2009) Correctors enhance maturation of DeltaF508 CFTR by promoting interactions between the two halves of the molecule. Biochemistry 48:9882–9890
Los EL, Deen PM, Robben JH (2010) Potential of nonpeptide (ant)agonists to rescue vasopressin V2 receptor mutants for the treatment of X-linked nephrogenic diabetes insipidus. J Neuroendocrinol 22:393–399
Madoux F, Janovick JA, Smithson D, Fargue S, Danpure CJ, Scampavia L, Chen YT, Spicer TP, Conn PM (2015) Development of a phenotypic high-content assay to identify pharmacoperone drugs for the treatment of primary hyperoxaluria type 1 by high-throughput screening. Assay Drug Dev Technol 13:16–24
Mah SJ, Cornell E, Mitchell NA, Fleck MW (2005) Glutamate receptor trafficking: endoplasmic reticulum quality control involves ligand binding and receptor function. J Neurosci 25:2215–2225
Malaga-Dieguez L, Yang Q, Bauer J, Pankevych H, Freissmuth M, Nanoff C (2010) Pharmacochaperoning of the A1 adenosine receptor is contingent on the endoplasmic reticulum. Mol Pharmacol 77:940–952
Martin GM, Chen PC, Devaraneni P, Shyng SL (2013) Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels. Front Physiol 4:386
Martínez-Limón A, Alriquet M, Lang W-H, Calloni G, Wittig I, Vabulas MR (2016) Recognition of enzymes lacking bound cofactor by protein quality control. Proc Natl Acad Sci 113:12156–12161
Matalonga L, Gort L, Ribes A (2017) Small molecules as therapeutic agents for inborn errors of metabolism. J Inherit Metab Dis 40:177–193
Mazzo F, Pistillo F, Grazioso G, Clementi F, Borgese N, Gotti C, Colombo S (2013) Nicotine-modulated subunit stoichiometry affects stability and trafficking of α3β4 nicotinic receptor. J Neurosci 33:12316–12328
Mendes HF, Cheetham ME (2008) Pharmacological manipulation of gain-of-function and dominant-negative mechanisms in rhodopsin retinitis pigmentosa. Hum Mol Genet 17:3043–3054
Mendoza JL, Schmidt A, Li Q, Nuvaga E, Barrett T, Bridges RJ, Feranchak AP, Brautigam CA, Thomas PJ (2012) Requirements for efficient correction of DeltaF508 CFTR revealed by analyses of evolved sequences. Cell 148:164–174
Merlie JP, Lindstrom J (1983) Assembly in vivo of mouse muscle acetylcholine receptor: identification of an alpha subunit species that may be an assembly intermediate. Cell 34:747–757
Morello JP, Bichet DG (2001) Nephrogenic diabetes insipidus. Annu Rev Physiol 63:607–630
Nashmi R, Dickinson ME, McKinney S, Jareb M, Labarca C, Fraser SE, Lester HA (2003) Assembly of alpha4beta2 nicotinic acetylcholine receptors assessed with functional fluorescently labeled subunits: effects of localization, trafficking, and nicotine-induced upregulation in clonal mammalian cells and in cultured midbrain neurons. J Neurosci 23:11554–11567
Nashmi R, Lester H (2007) Cell autonomy, receptor autonomy, and thermodynamics in nicotine receptor up-regulation. Biochem Pharmacol 74:1145–1154
Newton C, Whay A, McArdle C, Zhang M, van Koppen C, van de Lagemaat R, Segaloff D, Millar R (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, Sama RR, Kaushal S (2009) Calnexin improves the folding efficiency of mutant rhodopsin in the presence of pharmacological chaperone 11-cis-retinal. J Biol Chem 284:33333–33342
Nys M, Kesters D, Ulens C (2013) Structural insights into Cys-loop receptor function and ligand recognition. Biochem Pharmacol 86:1042–1053
Penn AC, Williams SR, Greger IH (2008) Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum. EMBO J 27:3056–3068
Perry MD, Ng CA, Phan K, David E, Steer K, Hunter MJ, Mann SA, Imtiaz M, Hill AP, Ke Y, Vandenberg JI (2016) Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations. J Physiol 594:4031–4049
Petäjä-Repo U, Hogue M, Bhalla S, Laperrière A, Morello J-P, Bouvier M (2002) Ligands act as pharmacological chaperones and increase the efficiency of delta opioid receptor maturation. EMBO J 21:1628–1637
Petaja-Repo UE, Hogue M, Bhalla S, Laperriere A, Morello JP, Bouvier M (2002) Ligands act as pharmacological chaperones and increase the efficiency of delta opioid receptor maturation. EMBO J 21:1628–1637
Petaja-Repo UE, Hogue M, Laperriere A, Walker P, Bouvier M (2000) Export from the endoplasmic reticulum represents the limiting step in the maturation and cell surface expression of the human delta opioid receptor. J Biol Chem 275:13727–13736
Porto C, Ferrara MC, Meli M, Acampora E, Avolio V, Rosa M, Cobucci-Ponzano B, Colombo G, Moracci M, Andria G, Parenti G (2012) Pharmacological enhancement of alpha-glucosidase by the allosteric chaperone N-acetylcysteine. Mol Ther 20:2201–2211
Rabeh WM, Bossard F, Xu H, Okiyoneda T, Bagdany M, Mulvihill CM, Du K, di Bernardo S, Liu Y, Konermann L et al (2012) Correction of both NBD1 energetics and domain interface is required to restore DeltaF508 CFTR folding and function. Cell 148:150–163
Rajamani S, Eckhardt LL, Valdivia CR, Klemens CA, Gillman BM, Anderson CL, Holzem KM, Delisle BP, Anson BD, Makielski JC, January CT (2006) Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine. Br J Pharmacol 149:481–489
Robert J, Auzan C, Ventura M, Clauser E (2005) Mechanisms of cell-surface rerouting of an endoplasmic reticulum-retained mutant of the vasopressin V1b/V3 receptor by a pharmacological chaperone. J Biol Chem 280:42198–42206
Rodrigues JV, Henriques BJ, Lucas TG, Gomes CM (2012) Cofactors and metabolites as protein folding helpers in metabolic diseases. Curr Top Med Chem 12:2546–2559
Sallette J, Bohler S, Benoit P, Soudant M, Pons S, Le Novere N, Changeux JP, Corringer PJ (2004) An extracellular protein microdomain controls up-regulation of neuronal nicotinic acetylcholine receptors by nicotine. J Biol Chem 279:18767–18775
Sallette J, Pons S, Devillers-Thiery A, Soudant M, Prado de Carvalho L, Changeux JP, Corringer PJ (2005) Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron 46:595–607
Santos-Sierra S, Kirchmair J, Perna AM, Reiss D, Kemter K, Roschinger W, Glossmann H, Gersting SW, Muntau AC, Wolber G, Lagler FB (2012) Novel pharmacological chaperones that correct phenylketonuria in mice. Hum Mol Genet 21:1877–1887
Schmidt J, Rossie S, Catterall WA (1985) A large intracellular pool of inactive Na channel alpha subunits in developing rat brain. Proc Natl Acad Sci U S A 82:4847–4851
She K, Ferreira JS, Carvalho AL, Craig AM (2012) Glutamate binding to the GluN2B subunit controls surface trafficking of N-methyl-D-aspartate (NMDA) receptors. J Biol Chem 287:27432–27445
Shin MH, Lim HS (2017) Screening methods for identifying pharmacological chaperones. Mol Biosyst 13:638–638
Smithson DC, Janovick JA, Conn PM (2013) Therapeutic rescue of misfolded/mistrafficked mutants: automation-friendly high-throughput assays for identification of pharmacoperone drugs of GPCRs. Methods Enzymol 521:3–16
Srinivasan R, Pantoja R, Moss FJ, Mackey ED, Son CD, Miwa J, Lester HA (2011) Nicotine up-regulates alpha4beta2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning. J Gen Physiol 137:59–79
Staudacher I, Wang L, Wan X, Obers S, Wenzel W, Tristram F, Koschny R, Staudacher K, Kisselbach J, Koelsch P et al (2011) hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine. Naunyn Schmiedebergs Arch Pharmacol 383:119–139
Tajima Y, Saito S, Ohno K, Tsukimura T, Tsujino S, Sakuraba H (2011) Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones. J Hum Genet 56:440–446
Taschenberger G, Mougey A, Shen S, Lester LB, LaFranchi S, Shyng SL (2002) Identification of a familial hyperinsulinism-causing mutation in the sulfonylurea receptor 1 that prevents normal trafficking and function of KATP channels. J Biol Chem 277:17139–17146
Thibodeau PH, Richardson JM 3rd, Wang W, Millen L, Watson J, Mendoza JL, Du K, Fischman S, Senderowitz H, Lukacs GL et al (2010) The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis. J Biol Chem 285:35825–35835
Thielen A, Oueslati M, Hermosilla R, Krause G, Oksche A, Rosenthal W, Schulein R (2005) The hydrophobic amino acid residues in the membrane-proximal C tail of the G protein-coupled vasopressin V2 receptor are necessary for transport-competent receptor folding. FEBS Lett 579:5227–5235
Ulloa-Aguirre A, Janovick JA, Miranda AL, Conn PM (2006) G-protein-coupled receptor trafficking: understanding the chemical basis of health and disease. ACS Chem Biol 1:631–638
Ulloa-Aguirre A, Zarinan T, Dias JA, Conn PM (2013) Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function. Mol Cell Endocrinol 382(1):411–423. [Epub 2013 Jun 24]. https://doi.org/10.1016/j.mce.2013.06.024
Valluru L, Xu J, Zhu Y, Yan S, Contractor A, Swanson GT (2005) Ligand binding is a critical requirement for plasma membrane expression of heteromeric kainate receptors. J Biol Chem 280:6085–6093
Van Craenenbroeck K, Clark SD, Cox MJ, Oak JN, Liu F, Van Tol HH (2005) Folding efficiency is rate-limiting in dopamine D4 receptor biogenesis. J Biol Chem 280:19350–19357
Van Craenenbroeck K, Gellynck E, Lintermans B, Leysen JE, Van Tol HH, Haegeman G, Vanhoenacker P (2006) Influence of the antipsychotic drug pipamperone on the expression of the dopamine D4 receptor. Life Sci 80:74–81
van den Eijnden MJ, Strous GJ (2007) Autocrine growth hormone: effects on growth hormone receptor trafficking and signaling. Mol Endocrinol 21:2832–2846
Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER et al (2011) Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 108:18843–18848
Veitia RA (2009) Dominant negative factors in health and disease. J Pathol 218:409–418
Wainwright CE, Elborn JS, Ramsey BW (2015) Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 373:1783–1784
Wang F, Nelson ME, Kuryatov A, Olale F, Cooper J, Keyser K, Lindstrom J (1998) Chronic nicotine treatment up-regulates human alpha3 beta2 but not alpha3 beta4 acetylcholine receptors stably transfected in human embryonic kidney cells. J Biol Chem 273:28721–28732
Wang L, Dennis AT, Trieu P, Charron F, Ethier N, Hebert TE, Wan X, Ficker E (2009) Intracellular potassium stabilizes human ether-a-go-go-related gene channels for export from endoplasmic reticulum. Mol Pharmacol 75:927–937
Wang P, Eshaq RS, Meshul CK, Moore C, Hood RL, Leidenheimer NJ (2015) Neuronal gamma-aminobutyric acid (GABA) type A receptors undergo cognate ligand chaperoning in the endoplasmic reticulum by endogenous GABA. Front Cell Neurosci 9:188. https://doi.org/10.3389/fncel.2015.00188. eCollection 2015. PMID: 26041994
Wang Y, Loo TW, Bartlett MC, Clarke DM (2007) Modulating the folding of P-glycoprotein and cystic fibrosis transmembrane conductance regulator truncation mutants with pharmacological chaperones. Mol Pharmacol 71:751–758
Wellhauser L, Kim Chiaw P, Pasyk S, Li C, Ramjeesingh M, Bear CE (2009) A small-molecule modulator interacts directly with deltaPhe508-CFTR to modify its ATPase activity and conformational stability. Mol Pharmacol 75:1430–1438
White E, McKenna J, Cavanaugh A, Breitwieser GE (2009) Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants. Mol Endocrinol 23:1115–1123
Wilkie AO (1994) The molecular basis of genetic dominance. J Med Genet 31:89–98
Wuller S, Wiesner B, Loffler A, Furkert J, Krause G, Hermosilla R, Schaefer M, Schulein R, Rosenthal W, Oksche A (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
Yan F, Lin CW, Weisiger E, Cartier EA, Taschenberger G, Shyng SL (2004) Sulfonylureas correct trafficking defects of ATP-sensitive potassium channels caused by mutations in the sulfonylurea receptor. J Biol Chem 279:11096–11105
Yasuda D, Okuno T, Yokomizo T, Hori T, Hirota N, Hashidate T, Miyano M, Shimizu T, Nakamura M (2009) Helix 8 of leukotriene B4 type-2 receptor is required for the folding to pass the quality control in the endoplasmic reticulum. FASEB J 23:1470–1481
Young-Gqamana B, Brignol N, Chang HH, Khanna R, Soska R, Fuller M, Sitaraman SA, Germain DP, Giugliani R, Hughes DA et al (2013) Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients. PLoS One 8:e57631
Yu W, Kim Chiaw P, Bear CE (2011) Probing conformational rescue induced by a chemical corrector of F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutant. J Biol Chem 286:24714–24725
Zhang L, Button B, Gabriel SE, Burkett S, Yan Y, Skiadopoulos MH, Dang YL, Vogel LN, McKay T, Mengos A et al (2009) CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. PLoS Biol 7:e1000155
Zhao J, Ziane R, Chatelier A, O’Leary ME, Chahine M (2007) Lidocaine promotes the trafficking and functional expression of Na(v)18 sodium channels in mammalian cells. J Neurophysiol 98:467–477
Zimran A, Altarescu G, Elstein D (2013) Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. Blood Cells Mol Dis 50:134–137
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The authors declare no competing financial interests. The support of NIH is gratefully acknowledged.
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Leidenheimer, N.J. (2017). Pharmacological Chaperones: Beyond Conformational Disorders. In: Ulloa-Aguirre, A., Tao, YX. (eds) Targeting Trafficking in Drug Development. Handbook of Experimental Pharmacology, vol 245. Springer, Cham. https://doi.org/10.1007/164_2017_68
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