Pharmacology of ORAI channels as a tool to understand their physiological functions

Bogeski, Ivan and Al-Ansary, Dalia and Qu, Bin and Niemeyer, Barbara A. and Hoth, Markus and Peinelt, Christine (2010) Pharmacology of ORAI channels as a tool to understand their physiological functions. Expert Review of Clinical Pharmacology, 3 (3). pp. 291-303. ISSN 1751-2433

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Depletion of inositol 1,4,5 trisphosphate-sensitive Ca2+ stores generates a yet unknown signal, which leads to increase in Ca2+ influx
in different cell types [J.W. Putney Jr., A model for receptor-regulated calcium entry, Cell Calcium 7 (1986) 1–12]. Here, we describe a
mechanism that modulates this store-operated Ca2+ entry (SOC). Ca2+ influx leads to inhibition of protein tyrosine phosphatase 1B (PTP1B)
activity in HEK 293 cells [L. Sternfeld, et al., Tyrosine phosphatase PTP1B interacts with TRPV6 in vivo and plays a role in TRPV6-mediated
calcium influx in HEK293 cells, Cell Signal 17 (2005) 951–960]. Since Ca2+ does not directly inhibit PTP1B, we assumed an intermediate
signal, which links the rise in cytosolic Ca2+ concentration and PTP1B inhibition.We now show that Ca2+ influx is followed by generation of
reactive oxygen species (ROS) and that it is reduced in cells preincubated with catalase. Furthermore, Ca2+-dependent inhibition of PTP1B
can be abolished in the presence of catalase. H2O2 (100�M) directly added to cells inhibits PTP1B and leads to increase in Ca2+ influx after
store depletion. PP1, an inhibitor of the Src family tyrosine kinases, prevents H2O2-induced Ca2+ influx.
Our results show that ROS act as fine tuning modulators of Ca2+ entry. We assume that the Ca2+ influx channel or a protein involved in
its regulation remains tyrosine phosphorylated as a consequence of PTP1B inhibition by ROS. This leads to maintained Ca2+ influx in the
manner of a positive feedback loop.

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 10:45
Last Modified: 07 May 2013 12:37

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