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Science 310 (5747): 490-493

Copyright © 2005 by the American Association for the Advancement of Science

The ß-Glucuronidase Klotho Hydrolyzes and Activates the TRPV5 Channel

Q. Chang, S. Hoefs, A. W. van der Kemp, C. N. Topala, R. J. Bindels, J. G. Hoenderop*

Abstract: Blood calcium concentration is maintained within a narrow range despite large variations in dietary input and body demand. The Transient Receptor Potential ion channel TRPV5 has been implicated in this process. We report here that TRPV5 is stimulated by the mammalian hormone klotho. Klotho, a ß-glucuronidase, hydrolyzes extracellular sugar residues on TRPV5, entrapping the channel in the plasma membrane. This maintains durable calcium channel activity and membrane calcium permeability in kidney. Thus, klotho activates a cell surface channel by hydrolysis of its extracellular N-linked oligosaccharides.

Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, Netherlands.

* To whom correspondence should be addressed. E-mail: J.Hoenderop{at}ncmls.ru.nl


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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S.-K. Cha, B. Ortega, H. Kurosu, K. P. Rosenblatt, M. Kuro-o, and C.-L. Huang (2008)
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   Abstract »    Full Text »    PDF »
Expression and Function of the HNK-1 Carbohydrate.
I. Morita, Y. Kizuka, S. Kakuda, and S. Oka (2008)
J. Biochem. 143, 719-724
   Abstract »    Full Text »    PDF »
A translocation causing increased {alpha}-Klotho level results in hypophosphatemic rickets and hyperparathyroidism.
C. A. Brownstein, F. Adler, C. Nelson-Williams, J. Iijima, P. Li, A. Imura, Y.-i. Nabeshima, M. Reyes-Mugica, T. O. Carpenter, and R. P. Lifton (2008)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging.
H. Liu, M. M Fergusson, R. M. Castilho, J. Liu, L. Cao, J. Chen, D. Malide, I. I. Rovira, D. Schimel, C. J. Kuo, et al. (2007)
Science 317, 803-806
   Abstract »    Full Text »    PDF »
Klotho spins the thread of life--what does Klotho do to the receptors of fibroblast growth factor-23 (FGF23)?.
T. B. Drueke and D. Prie (2007)
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   Full Text »    PDF »
Hydromineral Neuroendocrinology: Role of TRPV ion channels in sensory transduction of osmotic stimuli in mammals.
W. Liedtke (2007)
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   Abstract »    Full Text »    PDF »
Extracellular pH Dynamically Controls Cell Surface Delivery of Functional TRPV5 Channels.
T. T. Lambers, E. Oancea, T. de Groot, C. N. Topala, J. G. Hoenderop, and R. J. Bindels (2007)
Mol. Cell. Biol. 27, 1486-1494
   Abstract »    Full Text »    PDF »
Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice.
H. Segawa, S. Yamanaka, Y. Ohno, A. Onitsuka, K. Shiozawa, F. Aranami, J. Furutani, Y. Tomoe, M. Ito, M. Kuwahata, et al. (2007)
Am J Physiol Renal Physiol 292, F769-F779
   Abstract »    Full Text »    PDF »
Klotho--a Common Link in Physiological and Rheumatoid Arthritis-Related Aging of Human CD4+ Lymphocytes.
J. M. Witkowski, M. Soroczynska-Cybula, E. Bryl, Z. Smolenska, and A. Jozwik (2007)
J. Immunol. 178, 771-777
   Abstract »    Full Text »    PDF »
Transient Receptor Potential Cation Channels in Disease.
B. Nilius, G. Owsianik, T. Voets, and J. A. Peters (2007)
Physiol Rev 87, 165-217
   Abstract »    Full Text »    PDF »
Trafficking and Assembly of the Cold-sensitive TRPM8 Channel.
I. Erler, D. M. M. Al-Ansary, U. Wissenbach, T. F. J. Wagner, V. Flockerzi, and B. A. Niemeyer (2006)
J. Biol. Chem. 281, 38396-38404
   Abstract »    Full Text »    PDF »
Transient receptor potential vanilloid channels functioning in transduction of osmotic stimuli.
W. Liedtke (2006)
J. Endocrinol. 191, 515-523
   Abstract »    Full Text »    PDF »
Tissue kallikrein stimulates Ca2+ reabsorption via PKC-dependent plasma membrane accumulation of TRPV5.
D. Gkika, C. N. Topala, Q. Chang, N. Picard, S. Thebault, P. Houillier, J. G. Hoenderop, and R. J. M. Bindels (2006)
EMBO J. 25, 4707-4716
   Abstract »    Full Text »    PDF »
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J. P. Schoeber, C. N. Topala, X. Wang, R. J. Diepens, T. T. Lambers, J. G. Hoenderop, and R. J. Bindels (2006)
J. Biol. Chem. 281, 29669-29674
   Abstract »    Full Text »    PDF »
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T. Nijenhuis, B. C. J. van der Eerden, U. Zugel, A. Steinmeyer, H. Weinans, J. G. J. Hoenderop, J. P. T. M. van Leeuwen, and R. J. M. Bindels (2006)
FASEB J 20, 2171-2173
   Abstract »    Full Text »    PDF »
Klotho, an important new factor for the activity of Ca2+ channels, connecting calcium homeostasis, ageing and uraemia.
E. Lewin and K. Olgaard (2006)
Nephrol. Dial. Transplant. 21, 1770-1772
   Full Text »    PDF »
Regulation of TRPV5 and TRPV6 by associated proteins.
S. F. J. van de Graaf, J. G. J. Hoenderop, and R. J. M. Bindels (2006)
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   Abstract »    Full Text »    PDF »
Glycosylation of the osmoresponsive transient receptor potential channel TRPV4 on Asn-651 influences membrane trafficking.
H. Xu, Y. Fu, W. Tian, and D. M. Cohen (2006)
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   Abstract »    Full Text »    PDF »
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Y.-i. Nabeshima (2006)
Sci. Aging Knowl. Environ. 2006, pe11
   Abstract »    Full Text »
Highlights from the Literature.
(2006)
Physiology 21, 3-5
   Full Text »    PDF »

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