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      Inhibitory effects of AG490 on H2O2-induced TRPM2-mediated Ca(2+) entry.

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          Abstract

          Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress-sensitive Ca(2+)-permeable channel that controls Ca(2+) signalling. The activation of Janus kinase 2 (Jak2) by oxidative stress is implicated in the production of inflammatory mediators. We found that AG490, a Jak2 inhibitor, had an inhibitory effect on H2O2-induced TRPM2 activation. The purpose of this study was to examine the underlying mechanisms of the inhibitory effects of AG490. Activation of TRPM2 in TRPM2-expressing human embryonic kidney 293 (TRPM2/HEK) cells or the human monocytic cell line U937 was monitored by fluorescence-based Ca(2+) imaging and patch-clamp techniques. Treatment with AG490 almost completely blocked H2O2-induced increase in intracellular Ca(2+) in TRPM2/HEK and U937 cells. In the patch-clamp study, AG490 inhibited the H2O2-evoked inward current but not the ADP-ribose-induced inward current in TRPM2/HEK cells. In contrast, Jak inhibitor 1 (pyridone 6) and staurosporine, both of which inhibit Jak2, had no effect on H2O2-induced increase in intracellular Ca(2+). Moreover, AG490 decreased intracellular reactive oxygen species level, which was measured by using a hydroperoxide-sensitive fluorescent dye, on incubation with H2O2. In the cell-free assay system, AG490 scavenged hydroxyl radicals but not H2O2. These findings indicate that AG490 significantly reduces H2O2-induced TRPM2 activation, presumably by scavenging hydroxyl radicals rather than Jak2-dependent mechanisms. Although transient receptor potential ankyrin 1 (TRPA1) channel is also activated by H2O2, the H2O2-induced Ca(2+) entry through TRPA1 was only slightly delayed by AG490. This validates the potential use of AG490, as one of the materials for characterizing the role of TRPM2 channels in pathological models.

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          Author and article information

          Journal
          Eur. J. Pharmacol.
          European journal of pharmacology
          1879-0712
          0014-2999
          Nov 5 2014
          : 742
          Affiliations
          [1 ] Laboratory of Pharmacology, Department of Clinical Pharmacy, Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066, Japan; Division of Physiology and Pathology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, Tokyo 142-8555, Japan. Electronic address: shun@hamayaku.ac.jp.
          [2 ] Division of Physiology and Pathology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
          [3 ] Department of Food and Nutrition Science, Sagami Women׳s Junior College, Kanagawa 252-0838, Japan.
          [4 ] Department of Oral Biology, Graduate School of Dentistry, Tohoku University, Sendai 980-8575, Japan.
          [5 ] Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
          [6 ] Department of Pharmacogenomics, Showa University School of Pharmacy, Tokyo 142-8555, Japan.
          [7 ] Laboratory of Pharmacology, Department of Clinical Pharmacy, Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066, Japan.
          Article
          S0014-2999(14)00628-1
          10.1016/j.ejphar.2014.08.023
          25179574
          5a38a70b-6ae6-4d4d-bd1b-cd0f729a4e9d
          Copyright © 2014 Elsevier B.V. All rights reserved.
          History

          AG490,Janus kinase 2,Oxidative stress,TRPA1,TRPM2
          AG490, Janus kinase 2, Oxidative stress, TRPA1, TRPM2

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