Inhibition of TRPV2 Channel Activation by NK-4, a Cryptocyanine Dye

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  • Koya-Miyata Satomi
    Development Section, Pharmaceutical Ingredients Department, Personal Healthcare Division, Hayashibara Co., Ltd.
  • Kohno Keizo
    Development Section, Pharmaceutical Ingredients Department, Personal Healthcare Division, Hayashibara Co., Ltd.
  • Morimoto Takashi
    Development Section, Pharmaceutical Ingredients Department, Personal Healthcare Division, Hayashibara Co., Ltd.
  • Harashima Akira
    Development Section, Pharmaceutical Ingredients Department, Personal Healthcare Division, Hayashibara Co., Ltd.
  • Iwata Yuko
    Department of Cardiac Physiology, National Cerebral and Cardiovascular Center
  • Ariyasu Toshio
    Development Section, Pharmaceutical Ingredients Department, Personal Healthcare Division, Hayashibara Co., Ltd.

Bibliographic Information

Other Title
  • クリプトシアニン色素NK-4によるTRPV2チャネル活性化抑制作用
  • クリプトシアニン シキソ NK-4 ニ ヨル TRPV2 チャネル カッセイカ ヨクセイ サヨウ

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<p>Transient receptor potential vanilloid 2 (TRPV2) channels are expressed and play functional roles in various immune cells. Physical stimuli leading to TRPV2 activation causes mast cell degranulation. Besides their roles in immune cells, it has been shown that TRPV2 channels are pathophysiologically relevant to degenerative muscular diseases such as dilated cardiomyopathy and muscular dystrophy. Hence, development of drug candidates that inhibit human TRPV2 activation is an urgent matter. NK-4, a cryptocyanine dye, inhibited agonist-induced TRPV2 activity in mouse TRPV2-transfected HEK293 cells. However, it remains unclear whether NK-4 exerts regulatory effects on the activation of human TRPV2 channels. In this study, we show that NK-4 inhibits intracellular Ca2+ increase in human TRPV2-transfected HEK293 cells preactivated with a TRPV2 agonist. The inhibitory effect of NK-4 (IC50=0.27 μM) on human TRPV2 activation was 74-fold stronger than that on mouse TRPV2 activation (IC50=20 μM). NK-4 also inhibited the agonist-induced TRPV2 expression at the plasma membrane, when the human TRPV2-expressing cells were stimulated with the agonist in the presence of NK-4. These results suggest that NK-4 abrogates the agonist-induced signaling events leading to human TRPV2 activation. Furthermore, TRPV2 agonist caused degranulation of RBL-2H3 cells, which represents a phenomenon related to physical urticarias. NK-4 suppressed the release of β-hexosaminidases upon degradation with IC50 of 1.9 μM, 35-fold lower than that determined with an anti-allergic drug, Epinastine. Our results suggest that NK-4 would be a potential therapeutic strategy to resolve dilated cardiomyopathy and its associated heart failure as well as physical urticarias.</p>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 142 (5), 535-546, 2022-05-01

    The Pharmaceutical Society of Japan

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