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Gramicidin A directly inhibits mammalian Na+/K+-ATPase

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Abstract

The linear pentadecapeptide gramicidin A forms an ion channel in the lipid bilayer to selectively transport monovalent cations. Nevertheless, we have surprisingly found that gramicidin A directly inhibits mammalian Na+/K+-ATPase. Gramicidin A inhibited ATP hydrolysis by Na+/K+-ATPase from porcine cerebral cortex at the IC50 value of 8.1 μM, while gramicidin S was approximately fivefold less active. The synthetic gramicidin A analog lacking N-terminal formylation and C-terminal ethanolamine exhibited a weaker inhibitory effect on the ATP-hydrolyzing activity of Na+/K+-ATPase than gramicidin A, indicating that these end modifications are necessary for gramicidin A to inhibit Na+/K+-ATPase activity. Moreover, Lineweaver–Burk analysis showed that gramicidin A exhibits a mixed type of inhibition. In addition to the most well-studied ionophore activity, our present study has disclosed a novel biological function of gramicidin A as a direct inhibitor of mammalian Na+/K+-ATPase activity.

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Acknowledgments

We are very grateful to Drs. Yoshikazu Tahara and Yutaro Hayashi for the gift of Na+/K+-ATPase. We thank Drs. Hisakazu Mihara and Tsuyoshi Takahashi for synthesizing gramicidin A analog and critical reading of the manuscript. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

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Authors and Affiliations

  1. Center for Biological Resources and Informatics, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan

    Yohei Takada & Takao Kataoka

  2. Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan

    Kentaro Matsuo & Takao Kataoka

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  1. Yohei Takada
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  2. Kentaro Matsuo
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  3. Takao Kataoka
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Correspondence to Takao Kataoka.

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Takada, Y., Matsuo, K. & Kataoka, T. Gramicidin A directly inhibits mammalian Na+/K+-ATPase. Mol Cell Biochem 319, 99–103 (2008). https://doi.org/10.1007/s11010-008-9882-6

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  • DOI: https://doi.org/10.1007/s11010-008-9882-6

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