ATP modulates Ca2+ uptake by TRPV6 and is counteracted by isoform-specific phosphorylation

Al-Ansary, Dalia and Bogeski, Ivan and Disteldorf, B. M. J. and Becherer, U. and Niemeyer, Barbara A. (2010) ATP modulates Ca2+ uptake by TRPV6 and is counteracted by isoform-specific phosphorylation. The FASEB Journal, 24 (2). pp. 425-435. ISSN 0892-6638

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Ca2� homeostasis requires balanced uptake and extrusion, and dysregulation leads to disease. TRPV6 channels are homeostasis regulators, are upregulated in certain cancers, and show an unusual allelespecific evolution in humans. To understand how Ca2� uptake can be adapted to changes in metabolic status, we investigate regulation of Ca2�-influx by ATP and phosphorylation. We show that ATP binds to TRPV6, reduces whole-cell current increments, and prevents channel rundown with an EC50 of 380 �M. By using both biochemical binding studies and patch-clamp analyses of wild-type and mutant channels, we have mapped one relevant site for regulation by ATP to residues within the ankyrin repeat domain (ARD) and identify an additional C-terminal binding region. Stimulation of PKC largely prevented the effects of ATP. This regulation requires PKC�II and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca2� influx. Decreases in ATP concentration or activation of PKC�II disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca2� overload.—Al-Ansary, D., Bogeski, I., Disteldorf, B. M. J., Becherer, U., Niemeyer, B. A. ATP modulates Ca2� uptake by TRPV6 and is counteracted by isoformspecific phosphorylation.

Item Type: Article
Subjects: Medical and Health Sciences > Basic medicine
Medical and Health Sciences > Health sciences
Divisions: Faculty of Medical Science
Depositing User: Ivan Bogeski
Date Deposited: 27 Nov 2012 10:46
Last Modified: 07 Oct 2013 10:00

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