Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy

Proceedings of the National Academy of Sciences of the United States of America

Volumn 110, Issue 52, 2013, Pages 21030-21035

  Janovick, Jo Ann ^a,b   Stewart, M David ^c,d   Jacob, Darla ^a   Martin, L D ^a   Deng, Jian Min ^c   Stewart, C Allison ^c   Wang, Ying ^c   Cornea, Anda ^a   Chavali, Lakshmi ^d   Lopez, Suhujey ^d   Mitalipov, Shoukhrat ^a   Kang, Eunju ^a   Lee, Hyo Sang ^a,f   Manna, Pulak R ^b   Stocco, Douglas M ^b   Behringer, Richard R ^c   Conn, P Michael ^a,b,e  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^b TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER   (United States)

^c UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^d University of Houston   (United States)

^e OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^f New Drug Development Center   (South Korea)

Author keywords

Intracellular trafficking; Protein misrouting; Protein trafficking

Indexed keywords

ANDROGEN; BIOCHEMICAL MARKER; CHOLESTEROL MONOOXYGENASE (SIDE CHAIN CLEAVING); GONADORELIN; GONADORELIN AGONIST; GONADORELIN RECEPTOR; LUTEINIZING HORMONE; TESTOSTERONE; TESTOSTERONE 17BETA DEHYDROGENASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL MEMBRANE; CONTROLLED STUDY; DRUG EFFICACY; ENDOPLASMIC RETICULUM; GENE; GENE EXPRESSION; GENE MUTATION; GNRHR GENE; HYPOGONADOTROPIC HYPOGONADISM; HYPOPHYSIS; INFUSION; LUTEINIZING HORMONE BLOOD LEVEL; MALE; MORPHOLOGY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FOLDING; PROTEIN TRANSPORT; PULSATILE HORMONE RELEASE; SPERM; SPERMATOGENESIS; STEROIDOGENESIS; TESTIS FUNCTION; TESTIS WEIGHT; TESTOSTERONE BLOOD LEVEL;

EID: 84891357083     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1315194110     Document Type: Article

References (28)

1. Castro-Fernández C, Maya-Núñez G, Conn PM (2005) Beyond the signal sequence: Protein routing in health and disease. Endocr Rev 26(4): 479-503.
2. Morello JP, Petäjä-Repo UE, Bichet DG, BouvierM(2000) Pharmacological chaperones: A new twist on receptor folding. Trends Pharmacol Sci 21(12): 466-469.
3. Conn PM, Ulloa-Aguirre A, Ito J, Janovick JA (2007) G protein-coupled receptor trafficking in health and disease: Lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol Rev 59(3): 225-250.
4. Janovick JA, et al. (2003) 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(2): 608-614.
5. Janovick JA, Maya-Nunez G, Conn PM (2002) Rescue of hypogonadotropic hypogonadism- causing and manufactured GnRH receptor mutants by a specific proteinfolding template: Misrouted proteins as a novel disease etiology and therapeutic target. J Clin Endocrinol Metab 87(7): 3255-3262.
6. Seminara SB, Hayes FJ, Crowley WF, Jr. (1998) Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): Pathophysiological and genetic considerations. Endocr Rev 19(5): 521-539.
7. Janovick JA, 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(13): 8417-8425.
8. Sharpe RM, McKinnell C, Kivlin C, Fisher JS (2003) Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood. Reproduction 125(6): 769-784.
9. Pask AJ, et al. (2005) A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-N-nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation. Mol Endocrinol 19(4): 972-981.
10. Janovick JA, Conn PM (2010) Salt bridge integrates GPCR activation with protein trafficking. Proc Natl Acad Sci USA 107(9): 4454-4458.
11. Arimura A, Shino M, de la Cruz KG, Rennels EG, Schally AV (1976) Effect of active and passive immunization with luteinizing hormone-releasing hormone on serum luteinizing hormone and follicle-stimulating hormone levels and the ultrastructure of the pituitary gonadotrophs in castrated male rats. Endocrinology 99(1): 291-303.
12. Saloniemi T, Jokela H, Strauss L, Pakarinen P, Poutanen M (2012) The diversity of sex steroid action: Novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models. J Endocrinol 212(1): 27-40.
13. 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(7): 1787-1797.
14. Leaños-Miranda A, Ulloa-Aguirre A, Ji TH, Janovick JA, Conn PM (2003) Dominantnegative 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(7): 3360-3367.
15. Arango NA, Lovell-Badge R, Behringer RR (1999) Targeted mutagenesis of the endogenous mouse Mis gene promoter: In vivo definition of genetic pathways of vertebrate sexual development. Cell 99(4): 409-419.
16. Ventura A, et al. (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445(7128): 661-665.
17. Stewart MD, et al. (2012) Mice harboring Gnrhr E90K, a mutation that causes protein misfolding and hypogonadotropic hypogonadism in humans, exhibit testis size reduction and ovulation failure. Mol Endocrinol 26(11): 1847-1856.
18. Ishii S, Yoshioka H, Mannen K, Kulkarni AB, Fan JQ (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(3): 250-257.
19. Matsuda J, et al. (2003) Chemical chaperone therapy for brain pathology in G(M1)- gangliosidosis. Proc Natl Acad Sci USA 100(26): 15912-15917.
20. Shiozuka C, et al. (2011) Increased globotriaosylceramide levels in a transgenic mouse expressing human alpha1, 4-galactosyltransferase and a mouse model for treating Fabry disease. J Biochem 149(2): 161-170.
21. Bernier V, et al. (2006) Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 17(1): 232-243.
22. Conn PM, Janovick JA (2009) Drug development and the cellular quality control system. Trends Pharmacol Sci 30(5): 228-233.
23. Conn PM, Janovick JA (2009) Trafficking and quality control of the gonadotropin releasing hormone receptor in health and disease. Mol Cell Endocrinol 299(2): 137-145.
24. 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(7):e22784.
25. Janovick JA, et al. (2009) Molecular mechanism of action of pharmacoperone rescue of misrouted GPCR mutants: The GnRH receptor. Mol Endocrinol 23(2): 157-168.
26. Janovick JA, et al. (2007) Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro. Mol Cell Endocrinol 272(1-2): 77-85.
27. 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.
28. 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(8): 930-937.