TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients

FASEB Journal

Volumn 28, Issue 4, 2014, Pages 1924-1937

  Noel, Sekoni D ^a   Abreu, Ana Paula ^a,b   Xu, Shuyun ^a   Muyide, Titilayo ^a   Gianetti, Elena ^c   Tusset, Cintia ^b   Carroll, Jessica ^a   Latronico, Ana Claudia ^b   Seminara, Stephanie B ^c   Carroll, Rona S ^a   Kaiser, Ursula B ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b UNIVERSITY OF SÃO PAULO   (Brazil)

^c MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

GPCR; Hypogonadotropic hypogonadism; Neurokinin B; Tachykinins

Indexed keywords

G PROTEIN COUPLED RECEPTOR; GONADORELIN; GUANINE NUCLEOTIDE BINDING PROTEIN; INOSITOL PHOSPHATE; INTERLEUKIN 3; NEUROKININ 3 RECEPTOR; NEUROKININ A; NEUROKININ B; TACHYKININ; TACHYKININ RECEPTOR; TACHYKININ RECEPTOR 3; UNCLASSIFIED DRUG;

AMINO ACID SUBSTITUTION; ARTICLE; BINDING ASSAY; CONTROLLED STUDY; COS 7 CELL LINE; FLUORESCENCE RESONANCE ENERGY TRANSFER; GONADORELIN DEFICIENCY; GONADORELIN RELEASE; HEK293 CELL LINE; HORMONE DEFICIENCY; HUMAN; HUMAN CELL; INTRACELLULAR SIGNALING; LIGAND BINDING; LOSS OF FUNCTION MUTATION; LUTEINIZING HORMONE RELEASE; MISSENSE MUTATION; NEUROENDOCRINE SYSTEM; PRIORITY JOURNAL; PROTEIN SUBUNIT; RECEPTOR BINDING; SITE DIRECTED MUTAGENESIS; STRUCTURE ACTIVITY RELATION; TRANSIENT TRANSFECTION; WHOLE CELL;

GPCR; HYPOGONADOTROPIC HYPOGONADISM; NEUROKININ B; TACHYKININS;

ANIMALS; BINDING SITES; BINDING, COMPETITIVE; BLOTTING, WESTERN; CELL MEMBRANE; COS CELLS; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; FLUORESCENCE RESONANCE ENERGY TRANSFER; GONADOTROPIN-RELEASING HORMONE; GTP-BINDING PROTEIN ALPHA SUBUNITS, GQ-G11; HEK293 CELLS; HUMANS; INOSITOL PHOSPHATES; LUMINESCENT PROTEINS; MICROSCOPY, FLUORESCENCE; MUTATION, MISSENSE; NEUROKININ B; PHOSPHORYLATION; PROTEIN MULTIMERIZATION; RECEPTORS, NEUROKININ-3; SIGNAL TRANSDUCTION;

EID: 84901008986     PISSN: 08926638     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.13-240630     Document Type: Article

References (87)

1. Chang, M. M., Leeman, S. E., and Niall, H. D. (1971) Aminoacid sequence of substance P. Nat. New Biol. 232, 86-87
2. Nawa, H., Doteuchi, M., Igano, K., Inouye, K., and Nakanishi, S. (1984) Substance K: a novel mammalian tachykinin that differs from substance P in its pharmacological profile. Life Sci. 34, 1153-1160
3. Kangawa, K., Minamino, N., Fukuda, A., and Matsuo, H. (1983) Neuromedin K: a novel mammalian tachykinin identified in porcine spinal cord. Biochem. Biophys. Res. Commun. 114, 533-540
4. Severini, C., Improta, G., Falconieri-Erspamer, G., Salvadori, S., and Erspamer, V. (2002) The tachykinin peptide family. Pharmacol. Rev. 54, 285-322
5. Sandoval-Guzman, T., and Rance, N. E. (2004) Central injection of senktide, an NK3 receptor agonist, or neuropeptide Y inhibits LH secretion and induces different patterns of Fos expression in the rat hypothalamus. Brain Res. 1026, 307-312
6. Krajewski, S. J., Anderson, M. J., Iles-Shih, L., Chen, K. J., Urbanski, H. F., and Rance, N. E. (2005) Morphologic evidence that neurokinin B modulates gonadotropin-releasing hormone secretion via neurokinin 3 receptors in the rat median eminence. J. Comp. Neurol. 489, 372-386
7. Rance, N. E. (2009) Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides 30, 111-122
8. Osakada, F., Kubo, K., Goto, K., Kanazawa, I., and Munekata, E. (1986) The contractile activities of neurokinin A, B and related peptides on smooth muscles. Eur. J. Pharmacol. 120, 201-208
9. D'Orleans-Juste, P., Dion, S., Drapeau, G., and Regoli, D. (1986) Different receptors are involved in the endothelium-mediated relaxation and the smooth muscle contraction of the rabbit pulmonary artery in response to substance P and related neurokinins. Eur. J. Pharmacol. 125, 37-44
10. Page, N. M., Woods, R. J., Gardiner, S. M., Lomthaisong, K., Gladwell, R. T., Butlin, D. J., Manyonda, I. T., and Lowry, P. J. (2000) Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia. Nature 405, 797-800
11. Simonsen, K. B., Juhl, K., Steiniger-Brach, B., and Nielsen, S. M. (2010) Novel NK(3) receptor antagonists for the treatment of schizophrenia and other CNS indications. Curr. Opin. Drug Discov. Devel. 13, 379-388
12. Dawson, L. A., and Smith, P. W. (2010) Therapeutic utility of NK3 receptor antagonists for the treatment of schizophrenia. Curr. Pharm. Des. 16, 344-357
13. Topaloglu, A. K., Reimann, F., Guclu, M., Yalin, A. S., Kotan, L. D., Porter, K. M., Serin, A., Mungan, N. O., Cook, J. R., Ozbek, M. N., Imamoglu, S., Akalin, N. S., Yuksel, B., O'Rahilly, S., and Semple, R. K. (2009) TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat. Genet. 41, 354-358
14. Guran, T., Tolhurst, G., Bereket, A., Rocha, N., Porter, K., Turan, S., Gribble, F. M., Kotan, L. D., Akcay, T., Atay, Z., Canan, H., Serin, A., O'Rahilly, S., Reimann, F., Semple, R. K., and Topaloglu, A. K. (2009) Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor. J. Clin. Endocrinol. Metab. 94, 3633-3639
15. Gianetti, E., Tusset, C., Noel, S. D., Au, M. G., Dwyer, A. A., Hughes, V. A., Abreu, A. P., Carroll, J., Trarbach, E., Silveira, L. F., Costa, E. M., de Mendonca, B. B., de Castro, M., Lofrano, A., Hall, J. E., Bolu, E., Ozata, M., Quinton, R., Amory, J. K., Stewart, S. E., Arlt, W., Cole, T. R., Crowley, W. F., Kaiser, U. B., Latronico, A. C., and Seminara, S. B. (2010) TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J. Clin. Endocrinol. Metab. 95, 2857-2867
16. Young, J., Bouligand, J., Francou, B., Raffin-Sanson, M. L., Gaillez, S., Jeanpierre, M., Grynberg, M., Kamenicky, P., Chanson, P., Brailly-Tabard, S., and Guiochon-Mantel, A. (2010) TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. J. Clin. Endocrinol. Metab. 95, 2287-2295
17. Francou, B., Bouligand, J., Voican, A., Amazit, L., Trabado, S., Fagart, J., Meduri, G., Brailly-Tabard, S., Chanson, P., Lecomte, P., Guiochon-Mantel, A., and Young, J. (2011) Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations. PLoS One 6, e25614
18. Gerard, N. P., Eddy, R. L., Jr., Shows, T. B., and Gerard, C. (1990) The human neurokinin A (substance K) receptor. Molecular cloning of the gene, chromosome localization, and isolation of cDNA from tracheal and gastric tissues. J. Biol. Chem. 265, 20455-20462
19. Takeda, Y., Chou, K. B., Takeda, J., Sachais, B. S., and Krause, J. E. (1991) Molecular cloning, structural characterization and functional expression of the human substance P receptor. Biochem. Biophys. Res. Commun. 179, 1232-1240
20. Takahashi, K., Tanaka, A., Hara, M., and Nakanishi, S. (1992) The primary structure and gene organization of human substance P and neuromedin K receptors. Eur. J. Biochem. 204, 1025-1033
21. Gether, U., Johansen, T. E., and Schwartz, T. W. (1993) Chimeric NK1 (substance P)/NK3 (neurokinin B) receptors. Identification of domains determining the binding specificity of tachykinin agonists. J. Biol. Chem. 268, 7893-7898
22. Khawaja, A. M., and Rogers, D. F. (1996) Tachykinins: receptor to effector. Int. J. Biochem. Cell Biol. 28, 721-738
23. Wess, J. (1998) Molecular basis of receptor/G-protein-coupling selectivity. Pharmacol. Ther. 80, 231-264
24. Peeters, M. C., van Westen, G. J., Guo, D., Wisse, L. E., Muller, C. E., Beukers, M. W., and Ijzerman, A. P. (2011) GPCR structure and activation: an essential role for the first extracellular loop in activating the adenosine A2B receptor. FASEB J. 25, 632-643
25. Tan, C. M., Brady, A. E., Nickols, H. H., Wang, Q., and Limbird, L. E. (2004) Membrane trafficking of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 44, 559-609
26. Ferguson, S. S., Zhang, J., Barak, L. S., and Caron, M. G. (1998) Molecular mechanisms of G protein-coupled receptor desensitization and resensitization. Life Sci. 62, 1561-1565
27. Ganjiwale, A. D., Rao, G. S., and Cowsik, S. M. (2011) Molecular modeling of neurokinin B and tachykinin NK(3) receptor complex. J. Chem. Inf. Model. 51, 2932-2938
28. Zhang, Y. (2009) I-TASSER: fully automated protein structure prediction in CASP8. Proteins 77(Suppl. 9), 100-113
29. Goodman, R. L., Lehman, M. N., Smith, J. T., Coolen, L. M., de Oliveira, C. V., Jafarzadehshirazi, M. R., Pereira, A., Iqbal, J., Caraty, A., Ciofi, P., and Clarke, I. J. (2007) Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology 148, 5752-5760
30. Navarro, V. M., Gottsch, M. L., Chavkin, C., Okamura, H., Clifton, D. K., and Steiner, R. A. (2009) Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J. Neurosci. 29, 11859-11866
31. Wakabayashi, Y., Nakada, T., Murata, K., Ohkura, S., Mogi, K., Navarro, V. M., Clifton, D. K., Mori, Y., Tsukamura, H., Maeda, K., Steiner, R. A., and Okamura, H. (2010) Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat. J. Neurosci. 30, 3124-3132
32. Eghlidi, D. H., Haley, G. E., Noriega, N. C., Kohama, S. G., and Urbanski, H. F. (2010) Influence of age and 17beta-estradiol on kisspeptin, neurokinin B, and prodynorphin gene expression in the arcuate-median eminence of female rhesus macaques. Endocrinology 151, 3783-3794
33. Rance, N. E., Krajewski, S. J., Smith, M. A., Cholanian, M., and Dacks, P. A. (2010) Neurokinin B and the hypothalamic regulation of reproduction. Brain Res. 1364, 116-128
34. Amstalden, M., Coolen, L. M., Hemmerle, A. M., Billings, H. J., Connors, J. M., Goodman, R. L., and Lehman, M. N. (2010) Neurokinin 3 receptor immunoreactivity in the septal region, preoptic area and hypothalamus of the female sheep: colocalisation in neurokinin B cells of the arcuate nucleus but not in gonadotrophin-releasing hormone neurones. J. Neuroendocrinol. 22, 1-12
35. Kallo, I., Vida, B., Deli, L., Molnar, C. S., Hrabovszky, E., Caraty, A., Ciofi, P., Coen, C. W., and Liposits, Z. (2012) Co-localisation of kisspeptin with galanin or neurokinin B in afferents to mouse GnRH neurones. J. Neuroendocrinol. 24, 464-476
36. Todman, M. G., Han, S. K., and Herbison, A. E. (2005) Profiling neurotransmitter receptor expression in mouse gonadotropinreleasing hormone neurons using green fluorescent proteinpromoter transgenics and microarrays. Neuroscience 132, 703-712
37. Glidewell-Kenney, C. A., Shao, P. P., Iyer, A. K., Grove, A. M., Meadows, J. D., and Mellon, P. L. (2013) Neurokinin B causes acute GnRH secretion and repression of GnRH transcription in GT1-7 GnRH neurons. Mol. Endocrinol. 27, 437-454
38. Gaskins, G. T., Glanowska, K. M., and Moenter, S. M. (2013) Activation of neurokinin 3 receptors stimulates GnRH release in a location-dependent but kisspeptin-independent manner in adult mice. Endocrinology 154, 3984-3989
39. Billings, H. J., Connors, J. M., Altman, S. N., Hileman, S. M., Holaskova, I., Lehman, M. N., McManus, C. J., Nestor, C. C., Jacobs, B. H., and Goodman, R. L. (2010) Neurokinin B acts via the neurokinin-3 receptor in the retrochiasmatic area to stimulate luteinizing hormone secretion in sheep. Endocrinology 151, 3836-3846
40. Ramaswamy, S., Seminara, S. B., Ali, B., Ciofi, P., Amin, N. A., and Plant, T. M. (2010) Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with kisspeptin in the arcuate nucleus. Endocrinology 151, 4494-4503
41. Navarro, V. M., Castellano, J. M., McConkey, S. M., Pineda, R., Ruiz-Pino, F., Pinilla, L., Clifton, D. K., Tena-Sempere, M., and Steiner, R. A. (2011) Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat. Am. J. Physiol. Endocrinol. Metab. 300, E202-E210
42. Navarro, V. M., Gottsch, M. L., Wu, M., Garcia-Galiano, D., Hobbs, S. J., Bosch, M. A., Pinilla, L., Clifton, D. K., Dearth, A., Ronnekleiv, O. K., Braun, R. E., Palmiter, R. D., Tena-Sempere, M., Alreja, M., and Steiner, R. A. (2011) Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse. Endocrinology 152, 4265-4275
43. Kinsey-Jones, J. S., Grachev, P., Li, X. F., Lin, Y. S., Milligan, S. R., Lightman, S. L., and O'Byrne, K. T. (2012) The inhibitory effects of neurokinin B on GnRH pulse generator frequency in the female rat. Endocrinology 153, 307-315
44. Corander, M. P., Challis, B. G., Thompson, E. L., Jovanovic, Z., Loraine Tung, Y. C., Rimmington, D., Huhtaniemi, I. T., Murphy, K. G., Topaloglu, A. K., Yeo, G. S., O'Rahilly, S., Dhillo, W. S., Semple, R. K., and Coll, A. P. (2010) The effects of neurokinin B upon gonadotrophin release in male rodents. J. Neuroendocrinol. 22, 181-187
45. Kung, T. T., Crawley, Y., Jones, H., Luo, B., Gilchrest, H., Greenfeder, S., Anthes, J. C., Lira, S., Wiekowski, M., Cook, D. N., Hey, J. A., Egan, R. W., and Chapman, R. W. (2004) Tachykinin NK3-receptor deficiency does not inhibit pulmonary eosinophilia in allergic mice. Pharmacol. Res. 50, 611-615
46. Siuciak, J. A., McCarthy, S. A., Martin, A. N., Chapin, D. S., Stock, J., Nadeau, D. M., Kantesaria, S., Bryce-Pritt, D., and McLean, S. (2007) Disruption of the neurokinin-3 receptor (NK3) in mice leads to cognitive deficits. Psychopharmacology (Berl.) 194, 185-195
47. Nordquist, R. E., Delenclos, M., Ballard, T. M., Savignac, H., Pauly-Evers, M., Ozmen, L., and Spooren, W. (2008) Cognitive performance in neurokinin 3 receptor knockout mice. Psychopharmacology (Berl.) 198, 211-220
48. Yang, J. J., Caligioni, C. S., Chan, Y. M., and Seminara, S. B. (2012) Uncovering novel reproductive defects in neurokinin B receptor null mice: closing the gap between mice and men. Endocrinology 153, 1498-1508
49. Bedecarrats, G. Y., Linher, K. D., Janovick, J. A., Beranova, M., Kada, F., Seminara, S. B., Michael Conn, P., and Kaiser, U. B. (2003) Four naturally occurring mutations in the human GnRH receptor affect ligand binding and receptor function. Mol. Cell. Endocrinol. 205, 51-64
50. Gardner, T. A., Ferreira, J., Barlow, J., Lees, A. C., Parry, L., Vieira, I. C., Berenguer, E., Abramovay, R., Aleixo, A., Andretti, C., Aragao, L. E., Araujo, I., de Avila, W. S., Bardgett, R. D., Batistella, M., Begotti, R. A., Beldini, T., de Blas, D. E., Braga, R. F., Braga Dde, L., de Brito, J. G., de Camargo, P. B., Campos dos Santos, F., de Oliveira, V. C., Cordeiro, A. C., Cardoso, T. M., de Carvalho, D. R., Castelani, S. A., Chaul, J. C., Cerri, C. E., Costa Fde, A., da Costa, C. D., Coudel, E., Coutinho, A. C., Cunha, D., D'Antona, A., Dezincourt, J., Dias-Silva, K., Durigan, M., Esquerdo, J. C., Feres, J., Ferraz, S. F., Ferreira, A. E., Fiorini, A. C., da Silva, L. V., Frazao, F. S., Garrett, R., Gomes Ados, S., Goncalves Kda, S., Guerrero, J. B., Hamada, N., Hughes, R. M., Igliori, D. C., Jesus Eda, C., Juen, L., Junior, M., de Oliveira Junior, J. M., de Oliveira Junior, R. C., Souza Junior, C., Kaufmann, P., Korasaki, V., Leal, C. G., Leitao, R., Lima, N., Almeida Mde, F., Lourival, R., Louzada, J., Mac Nally, R., Marchand, S., Maues, M. M., Moreira, F. M., Morsello, C., Moura, N., Nessimian, J., Nunes, S., Oliveira, V. H., Pardini, R., Pereira, H. C., Pompeu, P. S., Ribas, C. R., Rossetti, F., Schmidt, F. A., da Silva, R., da Silva, R. C., da Silva, T. F., Silveira, J., Siqueira, J. V., de Carvalho, T. S., Solar, R. R., Tancredi, N. S., Thomson, J. R., Torres, P. C., Vaz-de-Mello, F. Z., Veiga, R. C., Venturieri, A., Viana, C., Weinhold, D., Zanetti, R., and Zuanon, J. (2013A social and ecological assessment of tropical land uses at multiple scales: the Sustainable Amazon Network. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368, 20120166
51. Wacker, J. L., Feller, D. B., Tang, X. B., Defino, M. C., Namkung, Y., Lyssand, J. S., Mhyre, A. J., Tan, X., Jensen, J. B., and Hague, C. (2008) Disease-causing mutation in GPR54 reveals the importance of the second intracellular loop for class A G-proteincoupled receptor function. J. Biol. Chem. 283, 31068-31078
52. Schliefenbaum, J., Kreile, A. K., Lohse, M. J., and Bunemann, M. (2008) G Protein coupled receptor kinase 2/3 separate Galphaq and Gbetagamma subunits during G protein activation. Biophys. J. 94, 665-667
53. Ng, P. C., and Henikoff, S. (2001) Predicting deleterious amino acid substitutions. Genome Res. 11, 863-874
54. Sunyaev, S., Ramensky, V., Koch, I., Lathe, W., 3rd, Kondrashov, A. S., and Bork, P. (2001) Prediction of deleterious human alleles. Hum. Mol. Genet. 10, 591-597
55. Thomas, P. D., Kejariwal, A., Campbell, M. J., Mi, H., Diemer, K., Guo, N., Ladunga, I., Ulitsky-Lazareva, B., Muruganujan, A., Rabkin, S., Vandergriff, J. A., and Doremieux, O. (2003) PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification. Nucleic Acids Res. 31, 334-341
56. Rasmussen, S. G., DeVree, B. T., Zou, Y., Kruse, A. C., Chung, K. Y., Kobilka, T. S., Thian, F. S., Chae, P. S., Pardon, E., Calinski, D., Mathiesen, J. M., Shah, S. T., Lyons, J. A., Caffrey, M., Gellman, S. H., Steyaert, J., Skiniotis, G., Weis, W. I., Sunahara, R. K., and Kobilka, B. K. (2011) Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477, 549-555
57. Katritch, V., Cherezov, V., and Stevens, R. C. (2013) Structurefunction of the G protein-coupled receptor superfamily. Annu. Rev. Pharmacol. Toxicol. 53, 531-556
58. Tao, Y. X. (2006) Inactivating mutations of G protein-coupled receptors and diseases: structure-function insights and therapeutic implications. Pharmacol. Therap. 111, 949-973
59. Franke, R. R., Sakmar, T. P., Oprian, D. D., and Khorana, H. G. (1988) A single amino acid substitution in rhodopsin (lysine 248-leucine) prevents activation of transducin. J. Biol. Chem. 263, 2119-2122
60. Punn, A., Chen, J., Delidaki, M., Tang, J., Liapakis, G., Lehnert, H., Levine, M. A., and Grammatopoulos, D. K. (2012) Mapping structural determinants within third intracellular loop that direct signaling specificity of type 1 corticotropin-releasing hormone receptor. J. Biol. Chem. 287, 8974-8985
61. McConalogue, K., Dery, O., Lovett, M., Wong, H., Walsh, J. H., Grady, E. F., and Bunnett, N. W. (1999) Substance P-induced trafficking of beta-arrestins. The role of beta-arrestins in endocytosis of the neurokinin-1 receptor. J. Biol. Chem. 274, 16257-16268
62. Schmidlin, F., Roosterman, D., and Bunnett, N. W. (2003) The third intracellular loop and carboxyl tail of neurokinin 1 and 3 receptors determine interactions with beta-arrestins. Am. J. Physiol. Cell Physiol. 285, C945-C958
63. Cezanne, L., Lecat, S., Lagane, B., Millot, C., Vollmer, J. Y., Matthes, H., Galzi, J. L., and Lopez, A. (2004) Dynamic confinement of NK2 receptors in the plasma membrane. Improved FRAP analysis and biological relevance. J. Biol. Chem. 279, 45057-45067
64. Chen, S., Lin, F., Xu, M., Hwa, J., and Graham, R. M. (2000) Dominant-negative activity of an alpha(1B)-adrenergic receptor signal-inactivating point mutation. EMBO J. 19, 4265-4271
65. Ward, B. K., Magno, A. L., Blitvich, B. J., Rea, A. J., Stuckey, B. G., Walsh, J. P., and Ratajczak, T. (2006) Novel mutations in the calcium-sensing receptor gene associated with biochemical and functional differences in familial hypocalciuric hypercalcaemia. Clin. Endocrinol. (Oxf.) 64, 580-587
66. Al-Salameh, A., Cetani, F., Pardi, E., Vulpoi, C., Pierre, P., de Calan, L., Guyetant, S., Jeunemaitre, X., and Lecomte, P. (2011) A novel mutation in the calcium-sensing receptor in a French family with familial hypocalciuric hypercalcaemia. Eur. J. Endocrinol. 165, 359-363
67. Pidasheva, S., D'Souza-Li, L., Canaff, L., Cole, D. E., and Hendy, G. N. (2004) CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcaemia. Hum. Mut. 24, 107-111
68. Bai, M., Trivedi, S., Kifor, O., Quinn, S. J., and Brown, E. M. (1999) Intermolecular interactions between dimeric calciumsensing receptor monomers are important for its normal function. Proc. Natl. Acad. Sci. U. S. A. 96, 2834-2839
69. Bai, M., Trivedi, S., and Brown, E. M. (1998) Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells. J. Biol. Chem. 273, 23605-23610
70. Tsai, B., Ye, Y., and Rapoport, T. A. (2002) Retro-translocation of proteins from the endoplasmic reticulum into the cytosol. Nat. Rev. Mol. Cell Biol. 3, 246-255
71. Gow, A., Friedrich, V. L., Jr., and Lazzarini, R. A. (1994) Many naturally occurring mutations of myelin proteolipid protein impair its intracellular transport. J. Neurosci. Res. 37, 574-583
72. Cheng, S. H., Gregory, R. J., Marshall, J., Paul, S., Souza, D. W., White, G. A., O'Riordan, C. R., and Smith, A. E. (1990) Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63, 827-834
73. Morello, J. P., Salahpour, A., Laperriere, A., Bernier, V., Arthus, M. F., Lonergan, M., Petaja-Repo, U., Angers, S., Morin, D., Bichet, D. G., and Bouvier, M. (2000) Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J. Clin. Invest. 105, 887-895
74. Conn, P. M., and Janovick, J. A. (2009) Trafficking and quality control of the gonadotropin releasing hormone receptor in health and disease. Mol. Cell. Endocrinol. 299, 137-145
75. Petaja-Repo, U. E., Hogue, M., Bhalla, S., Laperriere, A., Morello, J. P., and Bouvier, M. (2002) Ligands act as pharmacological chaperones and increase the efficiency of delta opioid receptor maturation. EMBO J. 21, 1628-1637
76. Hebert, D. N., and Molinari, M. (2007) In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol. Rev. 87, 1377-1408
77. Ellgaard, L., Molinari, M., and Helenius, A. (1999) Setting the standards: quality control in the secretory pathway. Science 286, 1882-1888
78. Horwich, A. (2002) Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions. J. Clin. Invest. 110, 1221-1232
79. Siffroi-Fernandez, S., Giraud, A., Lanet, J., and Franc, J. L. (2002) Association of the thyrotropin receptor with calnexin, calreticulin and BiP. Efects on the maturation of the receptor. Eur. J. Biochem. 269, 4930-4937
80. Achour, L., Labbe-Jullie, C., Scott, M. G., and Marullo, S. (2008) An escort for GPCRs: implications for regulation of receptor density at the cell surface. Trends Pharmacol. Sci. 29, 528-535
81. Mizrachi, D., and Segaloff, D. L. (2004) Intracellularly located misfolded glycoprotein hormone receptors associate with different chaperone proteins than their cognate wild-type receptors. Mol. Endocrinol. 18, 1768-1777
82. McLatchie, L. M., Fraser, N. J., Main, M. J., Wise, A., Brown, J., Thompson, N., Solari, R., Lee, M. G., and Foord, S. M. (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393, 333-339
83. Christopoulos, A., Christopoulos, G., Morfis, M., Udawela, M., Laburthe, M., Couvineau, A., Kuwasako, K., Tilakaratne, N., and Sexton, P. M. (2003) Novel receptor partners and function of receptor activity-modifying proteins. J. Biol. Chem. 278, 3293-3297
84. Bouschet, T., Martin, S., and Henley, J. M. (2005) Receptoractivity- modifying proteins are required for forward trafficking of the calcium-sensing receptor to the plasma membrane. J. Cell Sci. 118, 4709-4720
85. Saito, H., Kubota, M., Roberts, R. W., Chi, Q., and Matsunami, H. (2004) RTP family members induce functional expression of mammalian odorant receptors. Cell 119, 679-691
86. Janovick, J. A., Patny, A., Mosley, R., Goulet, M. T., Altman, M. D., Rush, T. S., 3rd, Cornea, A., and Conn, P. M. (2009) Molecular mechanism of action of pharmacoperone rescue of misrouted GPCR mutants: the GnRH receptor. Mol. Endocrinol. 23, 157-168
87. Maya-Nunez, G., Ulloa-Aguirre, A., Janovick, J. A., and Conn, P. M. (2012) Pharmacological chaperones correct misfolded gpcrs and rescue function: protein trafficking as a therapeutic target. Subcell. Biochem. 63, 263-289