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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Abstract

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
URI:	https://eprints.ugd.edu.mk/id/eprint/2204

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