Disease-causing Mutation in GPR54 Reveals the Importance of the Second Intracellular Loop for Class A G-protein-coupled Receptor Function
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The G-protein-coupled receptor (GPCR) GPR54 is essential for the development and maintenance of reproductive function in mammals. A point mutation (L148S) in the second intracellular loop (IL2) of GPR54 causes idiopathic hypogonadotropic hypogonadism, a disorder characterized by delayed puberty and infertility. Here, we characterize the molecular mechanism by which the L148S mutation causes disease and address the role of IL2 in Class A GPCR function. Biochemical, immunocytochemical, and pharmacological analysis demonstrates that the mutation does not affect the expression, ligand binding properties, or protein interaction network of GPR54. In contrast, diverse GPR54 functional responses are markedly inhibited by the L148S mutation. Importantly, the leucine residue at this position is highly conserved among class A GPCRs. Indeed, mutating the corresponding leucine of the alpha(1A)-AR recapitulates the effects observed with L148S GPR54, suggesting the critical importance of this hydrophobic IL2 residue for Class A GPCR functional coupling. Interestingly, co-immunoprecipitation studies indicate that L148S does not hinder the association of Galpha subunits with GPR54. However, fluorescence resonance energy transfer analysis strongly suggests that L148S impairs the ligand-induced catalytic activation of Galpha. Combining our data with a predictive Class A GPCR/Galpha model suggests that IL2 domains contain a conserved hydrophobic motif that, upon agonist stimulation, might stabilize the switch II region of Galpha. Such an interaction could promote opening of switch II of Galpha to facilitate GDP-GTP exchange and coupling to downstream signaling responses. Importantly, mutations that disrupt this key hydrophobic interface can manifest as human disease.
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The Leu148Ser substitution in the KiSS-1 receptor is located near the DRW(Y) motif, which has an important role in regulating activation and inactivation of many G-protein-coupled receptors.
“This substitution is located near the DRW(Y) motif, a motif that has an important role in regulating the activation and inactivation of many G-protein-coupled receptors.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [50]
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1 retracted
Johnston, C. A., & Siderovski, D. P. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608599104 · Cited by 38 · see citing works
RetractedHigh-Resolution Crystal Structure of an Engineered Human β 2 -Adrenergic G Protein–Coupled Receptor
Cherezov, V., Rosenbaum, D. M., Hanson, M. A., Rasmussen, S. G. F., Thian, F. S., Kobilka, T. S., Choi, H., Kühn, P., Weis, W. I., Kobilka, B. K., et al. (2007) · Science · doi:10.1126/science.1150577 · Cited by 3,280 · see citing works
The <i>GPR54</i> Gene as a Regulator of Puberty
Seminara, S. B., Messager, S., Chatzidaki, E. E., Thresher, R. R., Acierno, J. S., Shagoury, J. K., Bo-Abbas, Y., Kuohung, W., Schwinof, K. M., Hendrick, A. G., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa035322 · Cited by 2,557 · see citing works
Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., & Milgrom, E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834399100 · Cited by 2,431 · see citing works
Belchetz, P. E., Plant, T. M., Nakai, Y., Keogh, E. J., & Knobil, E. (1978) · Science · doi:10.1126/science.100883 · Cited by 1,385 · see citing works
Dynamics of gonadotropin-releasing hormone release during a pulse.
Moenter, S. M., Brand, R. M., MIDGLEY, A. R., & Karsch, F. J. (1992) · Endocrinology · doi:10.1210/endo.130.1.1727719 · Cited by 1,257 · see citing works
Heterotrimeric G protein activation by G-protein-coupled receptors
Oldham, W. M., & Hamm, H. E. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2299 · Cited by 1,174 · see citing works
A role for kisspeptins in the regulation of gonadotropin secretion in the mouse
Gottsch, M. L., Cunningham, M. J., Smith, J. T., Popa, S. M., Acohido, B. V., Crowley, W. F., Seminara, S., Clifton, D. K., & Steiner, R. A. (2004) · Endocrinology · doi:10.1210/en.2004-0431 · Cited by 1,161 · see citing works
Gray, J. J., Moughon, S. E., Wang, C., Schueler‐Furman, O., Kuhlman, B. A., Rohl, C. A., & Baker, D. A. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(03)00670-3 · Cited by 1,130 · see citing works
Irwig, M. S., Fraley, G. S., Smith, J. T., Acohido, B. V., Popa, S. M., Cunningham, M. J., Gottsch, M. L., Clifton, D. K., & Steiner, R. A. (2004) · Neuroendocrinology · doi:10.1159/000083140 · Cited by 913 · see citing works
Crystal Structure of the Catalytic Domains of Adenylyl Cyclase in a Complex with G sα ·GTPγS
Tesmer, J. J. G., Sunahara, R. K., Gilman, A. G., & Sprang, S. R. (1997) · Science · doi:10.1126/science.278.5345.1907 · Cited by 796 · see citing works
Tesmer, J. J. G., Berman, D. M., Gilman, A. G., & Sprang, S. R. (1997) · Cell · doi:10.1016/s0092-8674(00)80204-4 · Cited by 779 · see citing works
The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system
Funes, S., Hedrick, J. A., Vassileva, G., Markowitz, L., Abbondanzo, S., Golovko, A., Yang, S., Monsma, F. J., & Gustafson, E. L. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.11.066 · Cited by 675 · see citing works
Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males
Dhillo, W. S., Chaudhri, O. B., Patterson, M., Thompson, E. L., Murphy, K. G., Badman, M. K., McGowan, B. M., Amber, V., Patel, S., Ghatei, M. A., et al. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1468 · Cited by 656 · see citing works
A family of receptors coupled to guanine nucleotide regulatory proteins
Dohlman, H. G., Caron, M. G., & Lefkowitz, R. J. (1987) · Biochemistry · doi:10.1021/bi00384a001 · Cited by 634 · see citing works
Navarro, V. M., Castellano, J. M., Fernández-Fernández, R., Tovar, S., Roa, J., Mayen, A., Nogueiras, R., Vazquez, M. J., Barreiro, M. L., Magni, P., et al. (2005) · Endocrinology · doi:10.1210/en.2004-0836 · Cited by 449 · see citing works
The Highly Conserved DRY Motif of Class A G Protein-Coupled Receptors: Beyond the Ground State
Rovati, G. E., Capra, V., & Neubig, R. R. (2007) · Molecular Pharmacology · doi:10.1124/mol.106.029470 · Cited by 392 · see citing works
Semple, R. K., Achermann, J. C., Ellery, J., Farooqi, I. S., Karet, F. E., Stanhope, R. G., O’Rahilly, S., & Aparicio, S. A. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1418 · Cited by 291 · see citing works
Snapshot of Activated G Proteins at the Membrane: The Gα q -GRK2-Gßγ Complex
Tesmer, V. M., Kawano, T., Shankaranarayanan, A., Kozasa, T., & Tesmer, J. J. G. (2005) · Science · doi:10.1126/science.1118890 · Cited by 289 · see citing works
Evolutionary and Physiological Importance of Hub Proteins
Batada, N. N., Hurst, L. D., & Tyers, M. (2005) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0020088 · Cited by 284 · see citing works
Conn, P. M., Ulloa‐Aguirre, A., Ito, J., & Janovick, J. A. (2007) · Pharmacological Reviews · doi:10.1124/pr.59.3.2 · Cited by 242 · see citing works
Structure Modeling of All Identified G Protein–Coupled Receptors in the Human Genome
Zhang, Y., DeVries, M. E., & Skolnick, J. (2006) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0020013 · Cited by 236 · see citing works
Structural basis of function in heterotrimeric G proteins
Oldham, W. M., & Hamm, H. E. (2006) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583506004306 · Cited by 234 · see citing works
Regulation of G Protein–Coupled Receptor Signaling by Scaffold Proteins
Hall, R. A., & Lefkowitz, R. J. (2002) · Circulation Research · doi:10.1161/01.res.0000037000.74258.03 · Cited by 227 · see citing works
Hydrophobic amino acid in the i2 loop plays a key role in receptor-G protein coupling.
Moro, O., Lameh, J., Högger, P., & Sadée, W. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)41524-4 · Cited by 218 · see citing works
Membrane Trafficking of G Protein–Coupled Receptors
Tan, C. M., Brady, A. E., Nickols, H. H., Wang, Q., & Limbird, L. E. (2004) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.44.101802.121558 · Cited by 207 · see citing works
G-protein diseases furnish a model for the turn-on switch
Iiri, T., Farfel, Z., & Bourne, H. R. (1998) · Nature · doi:10.1038/27831 · Cited by 195 · see citing works
Arora, K. K., Sakai, A., & Catt, K. J. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.39.22820 · Cited by 153 · see citing works
Tao, Y. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.02.008 · Cited by 151 · see citing works
Receptor-Mediated Activation of Heterotrimeric G-Proteins: Current Structural Insights
Johnston, C. A., & Siderovski, D. P. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.034348 · Cited by 144 · see citing works
Cai, K., Itoh, Y., & Khorana, H. G. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051632898 · Cited by 140 · see citing works
Burstein, E. S., Spalding, T. A., & Brann, M. R. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.38.24322 · Cited by 124 · see citing works
Blin, N., Yun, J. S., & Wess, J. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.30.17741 · Cited by 116 · see citing works
Gáborik, Z., Jagadeesh, G., Zhang, M., Spät, A., Catt, K. J., & Hunyady, L. (2003) · Endocrinology · doi:10.1210/en.2002-0135 · Cited by 110 · see citing works
Marion, S., Oakley, R. H., Kim, K. M., Caron, M. G., & Barak, L. S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508074200 · Cited by 108 · see citing works
Costa, E. M. F., Bédécarrats, G. Y., Mendonca, B. B., Arnhold, I. J. P., Kaiser, U. B., & Latronico, A. C. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.6.7551 · Cited by 105 · see citing works
Daulat, A. M., Maurice, P., Froment, C., Guillaume, J., Broussard, C., Monsarrat, B., Delagrange, P., & Jockers, R. (2007) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m600298-mcp200 · Cited by 93 · see citing works
A cell-based immunocytochemical assay for monitoring kinase signaling pathways and drug efficacy
Chen, H., Kovar, J. L., Sissons, S. E., Cox, K. L., Matter, W. F., Chadwell, F., Luan, P., Vlahos, C. J., Schutz-Geschwender, A. R., & Olive, D. M. (2004) · Analytical Biochemistry · doi:10.1016/j.ab.2004.11.015 · Cited by 87 · see citing works
The Genetics of Hypogonadotropic Hypogonadism
Bhagavath, B., & Layman, L. C. (2007) · Seminars in Reproductive Medicine · doi:10.1055/s-2007-980221 · Cited by 70 · see citing works
Reproductive Medicine: Molecular, Cellular and Genetic Fundamentals
Penzias, A. S. (2003) · JAMA · doi:10.1001/jama.290.22.3005-a · Cited by 69 · cited 1× · see citing works
“A diverse network of signaling pathways have evolved within the hypothalamic-pituitary-gonadal axis to ensure precise neuroendocrine regulation of reproductive function in mammals (1).”
BackgroundBlood Pressure Is Regulated by an α1D-Adrenergic Receptor/Dystrophin Signalosome
Lyssand, J. S., DeFino, M. C., Tang, X., Hertz, A. L., Feller, D. B., Wacker, J. L., Adams, M. E., & Hague, C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801860200 · Cited by 60 · see citing works
Self-citationSeminara, S. B. (2006) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0139 · Cited by 55 · see citing works
Conn, P. M., Janovick, J. A., Brothers, S. P., & Knollman, P. E. (2006) · Journal of Endocrinology · doi:10.1677/joe.1.06771 · Cited by 40 · see citing works
New insights in the genetics of isolated hypogonadotropic hypogonadism
Iovane, A., Aumas, C., & de Roux, N. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.151u083 · Cited by 39 · see citing works
Kang, H., Lee, W., Choi, Y. H., Vukoti, K., Bang, W., & Yu, Y. G. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.02.040 · Cited by 39 · see citing works
Nanoff, C., Koppensteiner, R., Yang, Q., Fuerst, E., Ahorn, H., & Freissmuth, M. (2005) · Molecular Pharmacology · doi:10.1124/mol.105.016725 · Cited by 32 · see citing works
Zhou, H., Yan, F., Yamamoto, S., & Tai, H. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.1508 · Cited by 22 · see citing works
Geiser, A. H., Sievert, M. K., Guo, L., Grant, J. E., Krebs, M. P., Fotiadis, D., Engel, A. H., & Ruoho, A. E. (2006) · Protein Science · doi:10.1110/ps.062192306 · Cited by 16 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., and Milgrom, E. (2003) Proc. Natl. Acad. Sci. U. S. A 100, 10972-10976
- Cai, K., Itoh, Y., and Khorana, H. G. (2001) Proc. Natl. Acad. Sci. 98, 4877-4882
- Johnston, C. A., and Siderovski, D. P. (2007) Proc. Natl. Acad. Sci. U. S. A. 104, 2001-2006
Cited by
Sorted by citations
Kisspeptin Signaling in the Brain
Oakley, A. E., Clifton, D. K., & Steiner, R. A. (2009) · Endocrine Reviews · doi:10.1210/er.2009-0005 · Cited by 842 · see citing works
“By examining the efficacy of signaling in various models of Kiss1r mutations, one recent report has identified the IL2-10 residue as a key player in the structural rearrangement of Kiss1r upon binding of the ligand, kisspeptin (22).”
BackgroundKisspeptins and Reproduction: Physiological Roles and Regulatory Mechanisms
Pinilla, L., Aguilar, E., Diéguez, C., Millar, R. P., & Tena‐Sempere, M. (2012) · Physiological Reviews · doi:10.1152/physrev.00037.2010 · Cited by 802 · see citing works
“Nonetheless, the importance of the second intracellular loop for proper GPR54 signaling had been previously unveiled by the observation that a point L148S mutation in this region causes iHH in humans (401), and severely blunts ( 90% reduction) the ability of GPR54 to induce PI hydrolysis and to activate ERK1/2 upon Kp…”
BackgroundCXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling
Levoye, A., Balabanian, K., Baleux, F., Bachelerie, F., & Lagane, B. (2009) · Blood · doi:10.1182/blood-2008-12-196618 · Cited by 614 · see citing works
The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism
Bianco, S. D. C., & Kaiser, U. B. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.177 · Cited by 336 · see citing works
“This substitution is located near the DRW(Y) motif, a motif that has an important role in regulating the activation and inactivation of many G-protein-coupled receptors”
BackgroundSeyedabadi, M., Ghahremani, M. H., & Albert, P. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.05.006 · Cited by 148 · see citing works
MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors
Pasquier, J., Kamech, N., Lafont, A.-G., Vaudry, H., Rousseau, K., & Dufour, S. (2014) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0224 · Cited by 128 · see citing works
“Biochemical and pharmacological analyses have demonstrated that this Leu residue, which is highly conserved in class A GPCRs, is implicated in receptor coupling through hydrophobic interactions with the G a subunit (Wacker et al. 2008; Supplementary Figure 1).”
BackgroundRegulation of GPR54 Signaling by GRK2 and β-Arrestin
Pampillo, M., Camuso, N., Taylor, J. E., Szereszewski, J. M., Ahow, M. R., Zajac, M., Millar, R. P., Bhattacharya, M. M., & Babwah, A. V. (2009) · Molecular Endocrinology · doi:10.1210/me.2009-0013 · Cited by 121 · see citing works
“that has been shown to mediate GPR54 binding to G q (39).”
BackgroundBrioude, F., Bouligand, J., Trabado, S., Francou, B., Salenave, S., Kamenický, P., Brailly‐Tabard, S., Chanson, P., Guiochon‐Mantel, A., & Young, J. (2010) · European Journal of Endocrinology · doi:10.1530/eje-10-0083 · Cited by 113 · see citing works
Kirby, H. R., Maguire, J. J., Colledge, W. H., & Davenport, A. P. (2010) · Pharmacological Reviews · doi:10.1124/pr.110.002774 · Cited by 109 · see citing works
“Since then, other loss-of-function mutations have been documented, and more detailed molecular analysis has shown the L148S mutation to inhibit the catalytic activation of Gq but not to affect the trafficking, plasma membrane expression, or ligand binding properties of the receptor (Wacker et al., 2008).”
BackgroundPreininger, A. M., Meiler, J., & Hamm, H. E. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.04.011 · Cited by 104 · see citing works
“25 This particular IC2 loop residue has been shown to play an important role in physiology, as an L-to-S mutation in the residue that is homologous to F139 in the GPCR, GPR54, causes idiopathic hypogonadotropic hypogonadism, a disorder associated with delayed puberty and infertility.(64)”
BackgroundStructural basis of G protein–coupled receptor–G protein interactions
Hu, J., Wang, Y., Zhang, X., Lloyd, J. R., Li, J. H., Karpiak, J. D., Costanzi, S., & Wess, J. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.385 · Cited by 83 · see citing works
Kisspeptin signaling in the brain: Recent developments and future challenges
Tena‐Sempere, M. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.05.004 · Cited by 75 · see citing works
“importance of this domain for ligand-induced catalytic activation of G subunits, but not for receptor expression or ligand binding [16].”
Szereszewski, J. M., Pampillo, M., Ahow, M. R., Offermanns, S., Bhattacharya, M. M., & Babwah, A. V. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012964 · Cited by 71 · see citing works
“Recently, we reported that GPR54 couples to b-arrestin-2 via sequences in its second intracellular loop [4] and another study reported that the L148 residue in the second intracellular loop of GPR54 is required for the activation of Gq/11 [25].”
BackgroundChen, X., Yang, W. J., Fan, Y., Luo, J., Hong, K., Wang, Z., Yan, J., Chen, X., Lu, J., Benovic, J., et al. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01006.x · Cited by 66 · see citing works
“…(Moro et al., 1993), gonadotropicreleasing hormone receptor (Arora et al., 1995), 5-HT2C receptor (Berg et al., 2008), kisspeptin receptor (GPR54) (Wacker et al., 2008), and mouse EP2 and EP3 prostaglandin receptors (Sugimoto et al., 2004) revealed that the resulting mutant receptors were greatly…”
BackgroundInfluentialPhysiological Roles of the Kisspeptin/GPR54 System in the Neuroendocrine Control of Reproduction
Pineda, R., Aguilar, E., Pinilla, L., & Tena‐Sempere, M. (2010) · Progress in brain research · doi:10.1016/s0079-6123(08)81005-9 · Cited by 63 · see citing works
“…place recently, such as the characterization of the important roles of the intra-cellular loop 2 of GPR54 in the catalytic activation of Ga subunit (Wacker et al., 2008), and the ability of the GPR serine/threonine kinase 2, GRK2, and b-arrestin to modulate GPR54 signalling (Pampillo et al.,…”
BackgroundCellular mechanisms and integrative timing of neuroendocrine control of GnRH secretion by kisspeptin
Beltramo, M., Dardente, H., Cayla, X., & Caraty, A. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.10.015 · Cited by 63 · see citing works
Physiology and Disorders of Puberty
Styne, D. M., & Grumbach, M. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-29738-7.00025-3 · Cited by 55 · see citing works
The kisspeptin receptor: A key G-protein-coupled receptor in the control of the reproductive axis
Franssen, D., & Tena‐Sempere, M. (2018) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2018.01.005 · Cited by 50 · see citing works
Dynamic Kisspeptin Receptor Trafficking Modulates Kisspeptin-Mediated Calcium Signaling
Min, L., Soltis, K. A., Reis, A. C. S., Xu, S., Kuohung, W., Jain, M., Carroll, R. S., & Kaiser, U. B. (2013) · Molecular Endocrinology · doi:10.1210/me.2013-1165 · Cited by 47 · see citing works
“In an earlier study, Western blot analysis of KISS1R-GFP revealed a dominant band close to 75 kDa (50).”
BackgroundMethodCho, S., Wang, Y., Rodríguez, M., Tan, K., Zhang, W., Luo, J., Li, D., & Liu, M. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0329 · Cited by 47 · see citing works
G protein-coupled receptors involved in GnRH regulation: Molecular insights from human disease
Noel, S. D., & Kaiser, U. B. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.06.022 · Cited by 43 · see citing works
“, 2003) but does not affect KISS1R expression or ligand binding capabilities (Wacker et al., 2008).”
InfluentialCannabinoid receptor interacting protein (CRIP1a) attenuates CB1R signaling in neuronal cells
Blume, L. C., Eldeeb, K., Bass, C. E., Selley, D. E., & Howlett, A. C. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.11.006 · Cited by 42 · see citing works
“Total CB1R, CRIP1a, ERK1/2, and phosphoERK1/2 protein levels were quantified using a 96-well format “In-cell-Western” immunocytochemistry technique [18].”
MethodRecent methodological advances in the discovery of GPCR-associated protein complexes
Daulat, A. M., Maurice, P., & Jockers, R. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.10.009 · Cited by 40 · see citing works
Yang, L.-K., Hou, Z.-S., & Tao, Y. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165973 · Cited by 37 · see citing works
“One KISS1R mutation associated with IHH and infertility, L148S, has been shown to impact on the receptor with strong uncoupling from Gαq/11-dependent IP accumulation (downstream metabolite of IP3) although it does not affect receptor cell surface expression and ligand binding [215, 221].”
BackgroundFunctions of the DRY motif and intracellular loop 2 of human melanocortin 3 receptor
Huang, H., & Tao, Y. (2014) · Journal of Molecular Endocrinology · doi:10.1530/jme-14-0184 · Cited by 36 · see citing works
“2011) and GPR54 (L148S; Wacker et al. 2008).”
Ahow, M. R., Min, L., Pampillo, M., Nash, C. P., Wen, J., Soltis, K. A., Carroll, R. S., Glidewell-Kenney, C., Mellon, P. L., Bhattacharya, M. M., et al. (2014) · Endocrinology · doi:10.1210/en.2014-1304 · Cited by 36 · see citing works
Babwah, A. V., Navarro, V. M., Ahow, M. R., Pampillo, M., Nash, C. P., Fayazi, M., Calder, M. D., Elbert, A., Urbanski, H. F., Wettschureck, N., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0041-15.2015 · Cited by 35 · see citing works
“…via G s and G i/o (Kotani et al., 2001; Muir et al., 2001) and among the remaining G q family members [G 14 and G 15 (mouse)/16 (human)], whereas Kiss1r can signal via G 15/16 (Kotani et al., 2001; Wacker et al., 2008), it does not appear to do so via G 14 (A. Babwah, unpublished observations).”
BackgroundKISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis
Millar, R. P., & Babwah, A. V. (2015) · Neuroendocrinology · doi:10.1159/000381457 · Cited by 35 · see citing works
KISS1 in metastatic cancer research and treatment: potential and paradoxes
Ly, T., Harihar, S., & Welch, D. R. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09868-9 · Cited by 35 · see citing works
“KISS1R is typically coupled with Gαq/11 but can also associate with another Gαq member, Gα15/16, in hematopoietic organs [3, 50].”
BackgroundStyne, D. M., & Grumbach, M. M. (2011) · Elsevier eBooks · doi:10.1016/b978-1-4377-0324-5.00025-0 · Cited by 34 · see citing works
Novel, Gel-free Proteomics Approach Identifies RNF5 and JAMP as Modulators of GPCR Stability
Roy, S. J., Glazkova, I., Fréchette, L., Iorio‐Morin, C., Binda, C., Pétrin, D., Trieu, P., Robitaille, M., Angers, S., Hébert, T. E., et al. (2013) · Molecular Endocrinology · doi:10.1210/me.2013-1091 · Cited by 33 · see citing works
“Previous gel-free proteomic analyses of GPCRs were used successfully to identify novel interacting partners (69, 70).”
BackgroundZheng, C., Chen, L., Chen, X., He, X., Yang, J., Shi, Y., & Zhou, N. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063262 · Cited by 33 · see citing works
Clayton, C. C., Bruchas, M. R., Lee, M. L., & Chavkin, C. (2009) · Molecular Pharmacology · doi:10.1124/mol.109.060558 · Cited by 32 · see citing works
“Although the c-terminal tail and 3 loop have been implicated in G-protein activation (Johnson and Siderovski, 2007), it is also believed that agonists can act by changing the conformation of the GPCR 2 loop to activate the switch on the G-protein, remove the GDP block required for G-protein activation, or stabilize nu…”
BackgroundModeling the possible conformations of the extracellular loops in G‐protein‐coupled receptors
Nikiforovich, G. V., Taylor, C. M., Marshall, G. R., & Baranski, T. (2009) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.22537 · Cited by 29 · see citing works
“The Xray crystal conformations of the various ligands were used in the calculations (carazol, (2S)-1-(9H-carbazol-4-yloxy)3-(isopropylamino)propan-2-ol for b2AR; cyanopindolol, 4-{[(2S)-3-(tert-butylamino)-2-hydroxypropyl]oxy}- 3Hindole-2-carbonitrile for b1AR, and ZMA, 4-{2-[(7amino-2-furan-2-yl[1,2,4]triazolo[1,5-a]…”
MethodLyssand, J. S., Whiting, J. L., Lee, K.-S., Kastl, R., Wacker, J. L., Bruchas, M. R., Miyatake, M., Langeberg, L. K., Chavkin, C., Scott, J. D., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010819107 · Cited by 28 · see citing works
“Radioligand binding assays and ERK1/ 2 phosphorylation assays have been previously described (10, 45).”
MethodSelf-citationKe, R., Ma, X., & Lee, L. T. O. (2018) · Peptides · doi:10.1016/j.peptides.2018.09.007 · Cited by 24 · see citing works
Muscarinic receptor family interacting proteins: Role in receptor function
Borroto‐Escuela, D. O., Correia, P. A., Romero‐Fernandez, W., Narváez, M., Fuxé, K., Ciruela, F., & Garriga, P. (2010) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2010.11.025 · Cited by 24 · see citing works
The role of kisspeptin system in cancer biology
Stathaki, M., Stamatiou, M.-E., Magioris, G., Simantiris, S., Syrigos, N. K., Dourakis, S. P., Koutsilieris, M., & Armakolas, A. (2019) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2019.07.015 · Cited by 23 · see citing works
Yang, L., & Tao, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207611 · Cited by 20 · see citing works
“Impaired receptor activation caused by mutations on the corresponding position has been shown in other GPCRs, such as MC3R [20], β2-AR [52], and G-protein coupled receptor 54 [57].”
BackgroundPeng, Z., Tang, Y., Luo, H., Jiang, F., Yang, J., Sun, L., & Li, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.223784 · Cited by 20 · see citing works
Breuer, O., Abdulhadi‐Atwan, M., Zeligson, S., Fridman, H., Renbaum, P., Levy‐Lahad, E., & Zangen, D. (2012) · European Journal of Endocrinology · doi:10.1530/eje-12-0127 · Cited by 20 · see citing works
Shen, S., Wang, D., Liu, H., He, X., Cao, Y., Chen, J., Li, S., Cheng, X., Xu, H. E., & Duan, J. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114389 · Cited by 19 · see citing works
The role of kisspeptin/GPR54 in the reproductive system.
Papaoiconomou, E., Msaouel, P., Makri, A., Diamanti‐Kandarakis, E., & Koutsilieris, M. (2011) · PubMed · Cited by 16 · see citing works
Recent advances in computational studies of GPCR-G protein interactions
Wang, J., & Miao, Y. (2019) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2018.11.011 · Cited by 16 · see citing works
“…Preininger et al., 2009; Schoneberg, Kostenis, Liu, Gudermann, & Wess, 1998; Slessareva & Graber, 2003; Valiquette, Parent, Loisel, & Bouvier, 1995; Wacker et al., 2008; Xiao et al., 1999), nuclear magnetic resonance (NMR) (Kim et al., 2013), hydrogen-deuterium exchange mass spectrometry (HDXMS)…”
TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH‐deficient patients
Noel, S. D., Abreu, A. P., Xu, S., Muyide, T., Gianetti, E., Tusset, C., Carroll, J., Latronico, A. C., Seminara, S. B., Carroll, R. S., et al. (2013) · The FASEB Journal · doi:10.1096/fj.13-240630 · Cited by 15 · see citing works
“To further investigate the loss of receptor signaling for R295S NK3R, we used a FRET-based assay to monitor receptor–Gq-protein interaction kinetics following ligand binding (51).”
MethodInfluentialMolecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations
Bianco, S. D. C., & Kaiser, U. B. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-6199-9_7 · Cited by 13 · see citing works
Linking receptor activation to changes in Sw I and II of Gα proteins
Hamm, H. E., Kaya, A. İ., Gilbert, J. A., & Preininger, A. M. (2013) · Journal of Structural Biology · doi:10.1016/j.jsb.2013.02.016 · Cited by 10 · see citing works
Study on the Mechanism of Sarsasapogenin in Treating Precocious Puberty by Regulating the HPG Axis
Hu, K., Sun, W., Li, Y., Zhang, B., Zhang, M., Guo, C., Hong-sheng, C., & Wang, X. (2020) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2020/1978043 · Cited by 10 · see citing works
“erefore, as long as the GPR54 receptor function is normal and has the property of high binding with the ligand, it can still cause the excitation of GnRH neurons [61].”
BackgroundGonadotropin-Releasing Hormones
Millar, R. P., & Tello, J. A. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-18907-1.00115-3 · Cited by 11 · see citing works
Zheng, C., Chen, L., Chen, X., He, X., Yang, J., Shi, Y., & Zhou, N. (2013) · PLoS ONE · doi:10.1371/annotation/11146424-f236-4fc6-85b2-cd393cfb6a94 · Cited by 9 · see citing works
Radomsky, T., Anderson, R. C., Millar, R. P., & Newton, C. L. (2024) · Journal of Neuroendocrinology · doi:10.1111/jne.13418 · Cited by 8 · see citing works
“5,148 Conversely, a homozygous variant (F272S) identified in six related individuals with CHH, was demonstrated to have significantly reduced cell surface expression in fluorescent microscopy experiments.”
Shimizu, K., Yonekawa, T., Yoshida, M., Miyazato, M., Miura, A., Sakoda, H., Yamaguchi, H., & Nakazato, M. (2017) · Journal of the Endocrine Society · doi:10.1210/js.2017-00277 · Cited by 8 · see citing works
“[12], the potency and efficacy of these peptides in KISS1R L148S-expressing cells was much less than those observed for wild-type–expressing cells.”
BackgroundReceptor Transduction Pathways Mediating Hormone Action
Kublaoui, B. M., & Levine, M. A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-62520-3.00003-8 · Cited by 7 · see citing works
Tandem Affinity Purification and Identification of GPCR-Associated Protein Complexes
Daulat, A. M., Maurice, P., & Jockers, R. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-126-0_23 · Cited by 7 · see citing works
Techniques for the Discovery of GPCR-Associated Protein Complexes
Daulat, A. M., Maurice, P., & Jockers, R. (2013) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-391862-8.00018-1 · Cited by 6 · see citing works
Millar, R. P., Newton, C. L., & Roseweir, A. K. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-375097-6.10002-2 · Cited by 6 · see citing works
Atre, I., Mizrahi, N., Hausken, K., Yom-Din, S., Hurvitz, A., Degani, G., & Levavi‐Sivan, B. (2020) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2020.113691 · Cited by 6 · see citing works
Relevance of augmented kisspeptin signaling through H364 KISS1R in central precocious puberty
Banerjee, A. A., Bhanarkar, S. R., Keshwani, R., Pande, S. S., Modi, D. N., Mehta, A. R., Bombe, S., Pathak, B. R., Joshi, B. N., Tandon, D., et al. (2023) · Gene · doi:10.1016/j.gene.2023.148016 · Cited by 5 · see citing works
Receptor transduction pathways mediating hormone action
Kublaoui, B. M., & Levine, M. A. (2014) · Elsevier eBooks · doi:10.1016/b978-1-4557-4858-7.00012-3 · Cited by 5 · see citing works
Chapter 2 Human Diseases Associated with GPR54 Mutations
Teles, M. G., Silveira, L. F. G., Bianco, S. D. C., & Latronico, A. C. (2009) · Progress in molecular biology and translational science · doi:10.1016/s1877-1173(09)88002-2 · Cited by 3 · see citing works
da Silva, L. M., Vandepas, L. E., & Bianco, S. D. C. (2011) · Journal of Visualized Experiments · doi:10.3791/2897 · Cited by 3 · see citing works
Aslam, S., Jahan, N., & Manzoor, J. (2015) · Pakistan Journal of Zoology · Cited by 3 · see citing works
G-Protein-Coupled Receptors: Their Expression, Function and Regulation in Insecticide Resistance
Li, T., & Liu, N. (2018) · ACS symposium series · doi:10.1021/bk-2018-1289.ch008 · Cited by 2 · see citing works
Gonadotropin-Releasing Hormones
Millar, R. P., Lu, Z.-L., & Pawson, A. J. (2010) · Elsevier eBooks · doi:10.1016/b978-1-4160-5583-9.00115-5 · Cited by 2 · see citing works
Development of Prediction Method for GPCR-G-protein Coupling Selectivity Using Amino Acid Properties
Yabuki, Y., Ikeda, M., Mukai-Ikeda, Y., & Ishida, Y. (2009) · The Open Structural Biology Journal · doi:10.2174/1874199100903020149 · Cited by 1 · see citing works
“Keywords: G-protein coupled receptor, G-protein, G-protein coupling selectivity, amino acid property, support vector machine.”
BackgroundPoursharif, A., Shabani, S., Vaziri, H., & Mirzapour, T. (2016) · Gene Reports · doi:10.1016/j.genrep.2016.12.009 · Cited by 1 · see citing works
KISS1 and Its G Protein-Coupled Receptor (GPR54) in Cancer Progression and Metastasis
Cho, S. G. (2012) · OakTrust (Texas A&M University Libraries)
Minneman, K. P. (2011) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.8746956.9263055
Development of Prediction Method for GPCRG-protein Coupling Selectivity Using Amino Acid Properties
Yabuki, Y., Ikeda, M., Mukai-Ikeda, Y., & Ishida, Y. (2009) · The Open Structural Biology Journal · doi:10.2174/1874199100903010149
- Authors
- 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., & Hague, C.
- Affiliations
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Hague, Chris
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 283
- Issue
- 45
- Pages
- 31068-31078
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2576551
- OpenAlex
- W1997180803
- Cited by
- 71
- References
- 48
- Citations by year
- 2024: 2 · 2023: 1 · 2021: 1 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 1 · 2016: 2 · 2015: 4 · 2014: 5 · 2013: 10 · 2012: 4
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Washington
- National Institutes of Health (5u54hd012629-31, 5t32gm007108-40, GM-07270, GM07108, GM07750, RO1 NS08174, NS08174, T32 GM07108)
- National Institute of General Medical Sciences (GM-07270, T32-GM07270, T32 GM07750, T32GM007270, T32GM007750, T-32 GM07108)
- National Institute of Neurological Disorders and Stroke (R01 NS08174, R01NS008174)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32 HD07453, U54-HD-12629, T32HD007453)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- GPR54, second intracellular loop, class A G protein-coupled receptors, idiopathic hypogonadotropic hypogonadism, G protein coupling, switch II, hydrophobic interface, alpha1A-adrenergic receptor, reproductive function, delayed puberty, infertility
- MeSH terms
- Receptors, Kisspeptin-1, Cell Line, Guanosine Diphosphate, Guanosine Triphosphate, Humans, Hypogonadism, Point Mutation, Amino Acid Substitution, Amino Acid Motifs, Genetic Diseases, Inborn, Receptors, G-Protein-Coupled, GTP-Binding Protein alpha Subunits, Hydrophobic and Hydrophilic Interactions
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