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Similarities and Differences between Organic Cation Inhibition of the Na,K-ATPase and PMCA
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    Similarities and Differences between Organic Cation Inhibition of the Na,K-ATPase and PMCA
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    Division of Biomedical Sciences, Department of Biological Sciences, Illinois State University, Normal, Illinois 61790-4120, Dalton Cardiovascular Research Center & Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, Department of Medical Pharmacology and Physiology, School of Medicine, and Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211
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    Biochemistry

    Cite this: Biochemistry 2006, 45, 44, 13331–13345
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    https://doi.org/10.1021/bi060667j
    Published October 13, 2006
    Copyright © 2006 American Chemical Society

    Abstract

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    The effects of three classes of organic cations on the inhibition of the plasma membrane Ca pump (PMCA) were determined and compared to inhibition of the Na pump. Quaternary amines (tetramethylammonium, tetraethylammonium, and tetrapropylammonium, TMA, TEA, and TPA, respectively) did not inhibit PMCA. This is not to imply that PMCA is inherently selective against monovalent cations because guanidine and tetramethylguanidine inhibited PMCA by competing with Ca2+. The divalent organic cation, ethyl diamine, inhibited PMCA but was not competitive with Ca2+. In contrast, propyl diamine did compete with Ca2+ and was about 10-fold more potent than butyl diamine in inhibiting PMCA. For the Na pump, both TEA and TPA inhibited, but TMA did not. TEA, guanidine, and tetramethylguanidine inhibition was competitive with Na+ for ATPase activation and with K+ for pNPPase activation, both of which are cytoplasmic substrate cation effects. Thus, these findings are consistent with TEA, guanidine, and tetramethylguanidine inhibiting from the cytoplasmic side of the Na pump; in contrast, we have previously shown that TPA did not inhibit from the cytoplasmic side. The divalent alkane diamines ethyl, propyl, and butyl diamine all inhibited the Na pump and all competed at the intracellular surface. The order of potency was ED > PD > BD consistent with an optimal size for binding; similarly, for the quaternary amines TMA is apparently too small to make appropriate contacts, and TPA is too large. Homology models based upon the high-resolution SERCA structure are included to contextualize the kinetic observations.

    Copyright © 2006 American Chemical Society

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     This work was supported by the following grants (listed alphabetic-ally):  American Heart Association 030161N (C.G.), AHA 0265293Z (X.Z.), AHA Predoctoral Fellowship 0315236Z (J.B.H.), National Institutes of Health DK37512 (M.A.M.), NIH, DK61529 (X.Z.) and NIH GM 061583 and NSF MCB-0347202 (C.G.). Software support from the Tripos, Inc. (St. Louis, MO) to X.Z. is also gratefully acknowledged.

     Illinois State University.

    §

     Dalton Cardiovascular Research Center & Department of Biochemistry, University of Missouri.

     Department of Medical Pharmacology and Physiology, School of Medicine, and Dalton Cardiovascular Research Center, University of Missouri.

    *

     To whom correspondence should be addressed:  Mark A. Milanick, Ph.D., Dalton Cardiovascular Research Center, 134 Research Park Drive, University of Missouri, Columbia, MO 65211. Phone:  (573) 882-8055. FAX:  573-884-4232. E-mail:  [email protected].

    Cited By

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    This article is cited by 8 publications.

    1. R. Daniel Peluffo, Rodolfo M. González-Lebrero, Sergio B. Kaufman, Sandhya Kortagere, Branly Orban, Rolando C. Rossi and Joshua R. Berlin . Quaternary Benzyltriethylammonium Ion Binding to the Na,K-ATPase: A Tool to Investigate Extracellular K+ Binding Reactions. Biochemistry 2009, 48 (34) , 8105-8119. https://doi.org/10.1021/bi900687u
    2. Kevin S. Stanley, Victoria C. Young, Craig Gatto, Pablo Artigas. External Ion Access in the Na/K Pump: Kinetics of Na+, K+, and Quaternary Amine Interaction. Biophysical Journal 2018, 115 (2) , 361-374. https://doi.org/10.1016/j.bpj.2018.06.007
    3. Ian M. Ratheal, Gail K. Virgin, Haibo Yu, Benoît Roux, Craig Gatto, Pablo Artigas. Selectivity of externally facing ion-binding sites in the Na/K pump to alkali metals and organic cations. Proceedings of the National Academy of Sciences 2010, 107 (43) , 18718-18723. https://doi.org/10.1073/pnas.1004214107
    4. Siddhartha Yaragatupalli, J. Fernando Olivera, Craig Gatto, Pablo Artigas. Altered Na + transport after an intracellular α-subunit deletion reveals strict external sequential release of Na + from the Na/K pump. Proceedings of the National Academy of Sciences 2009, 106 (36) , 15507-15512. https://doi.org/10.1073/pnas.0903752106
    5. Craig Gatto, Mark Milanick. Red blood cell Na pump: Insights from species differences. Blood Cells, Molecules, and Diseases 2009, 42 (3) , 192-200. https://doi.org/10.1016/j.bcmd.2009.01.011
    6. Neil A. Johnson, Fengli Liu, Phillip D. Weeks, Audrey E. Hentzen, Hilary P. Kruse, Jennifer J. Parker, Mette Laursen, Poul Nissen, Charles J. Costa, Craig Gatto. A tomato ER-type Ca2+-ATPase, LCA1, has a low thapsigargin-sensitivity and can transport manganese. Archives of Biochemistry and Biophysics 2009, 481 (2) , 157-168. https://doi.org/10.1016/j.abb.2008.11.010
    7. Craig Gatto, Krista L. Arnett, Mark A. Milanick. Divalent Cation Interactions with Na,K-ATPase Cytoplasmic Cation Sites: Implications for the para-Nitrophenyl Phosphatase Reaction Mechanism. Journal of Membrane Biology 2007, 216 (1) , 49-59. https://doi.org/10.1007/s00232-007-9028-x
    8. Matthew S. Reifenberger, Krista L. Arnett, Craig Gatto, Mark A. Milanick. Extracellular terbium and divalent cation effects on the red blood cell Na pump and chrysoidine effects on the renal Na pump. Blood Cells, Molecules, and Diseases 2007, 39 (1) , 7-13. https://doi.org/10.1016/j.bcmd.2007.02.012

    Biochemistry

    Cite this: Biochemistry 2006, 45, 44, 13331–13345
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi060667j
    Published October 13, 2006
    Copyright © 2006 American Chemical Society

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