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J. Biol. Chem., Vol. 279, Issue 25, 26351-26357, June 18, 2004

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80K-H as a New Ca²⁺ Sensor Regulating the Activity of the Epithelial Ca²⁺ Channel Transient Receptor Potential Cation Channel V5 (TRPV5)^*

Dimitra Gkika, Frank Mahieu, Bernd Nilius, Joost G. J. Hoenderop, and René J. M. Bindels¶

From the Department of Physiology, Nijmegen Centre for Molecular Life Sciences, University Medical Centre Nijmegen, NL-6500 HB Nijmegen, The Netherlands and Department of Physiology, Campus Gasthuisberg, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

The epithelial Ca²⁺ channel transient receptor potential cation channel V5 (TRPV5) constitutes the apical Ca²⁺ entry pathway in the process of active Ca²⁺ reabsorption. Ca²⁺ influx through TRPV5 is tightly controlled by modulators of Ca²⁺ homeostasis, including 1,25-dihydroxyvitamin D₃ and dietary Ca²⁺. However, little is known about intracellular proteins that interact with TRPV5 and directly regulate the activation of this channel. By the use of cDNA microarrays, the present study identified 80K-H as the first protein involved in the Ca²⁺-dependent control of the epithelial Ca²⁺ channel TRPV5. 80K-H was initially identified as a protein kinase C substrate, but its biological function remains to be established. We demonstrated a specific interaction between 80K-H and TRPV5, co-localization of both proteins in the kidney, and similar transcriptional regulation by 1,25-dihydroxyvitamin D₃ and dietary Ca²⁺. Furthermore, 80K-H directly bound Ca²⁺, and inactivation of its two EF-hand structures totally abolished Ca²⁺ binding. Electrophysiological studies using 80K-H mutants showed that three domains of 80K-H (the two EF-hand structures, the highly acidic glutamic stretch, and the His-Asp-Glu-Leu sequence) are critical determinants for TRPV5 activity. Importantly, inactivation of the EF-hand pair reduced the TRPV5-mediated Ca²⁺ current and increased the TRPV5 sensitivity to intracellular Ca²⁺, accelerating the feedback inhibition of the channel. None of the 80K-H mutants altered the TRPV5 plasma membrane localization nor the association of 80K-H with TRPV5, suggesting that 80K-H has a direct effect on TRPV5 activity. In conclusion, we report a novel function for 80K-H as a Ca²⁺ sensor controlling TRPV5 channel activity.

Received for publication, April 6, 2004 , and in revised form, April 19, 2004.

^* This work was supported by Grants Zon-Mw 016.006.001, Zon-Mw 902.18.298, NWO-ALW 810.38.004, and NWO-ALW 805.09.042 from the Dutch Organization of Scientific Research, by the Belgian Federal Government, the Flemish Government, and the Onderzoeksraad KU Leuven (GOA 99/07, F.W.O. G.0136.00; F.W.O. G.0172.03, Interuniversity Poles of Attraction Program, IUAP, GOA 2004/07). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: 160 Cell Physiology, University Medical Centre Nijmegen, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands. Tel: 31-24-361-4211; Fax: 31-24-361-6413; E-mail: r.bindels{at}ncmls.kun.nl.

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