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Expression of the Voltage-Gated Sodium Channel NaV1.5 in the Macrophage Late Endosome Regulates Endosomal Acidification¹

Michael D. Carrithers^2,*, Sulayman Dib-Hajj^*,¶, Lisette M. Carrithers^*, Gouzel Tokmoulina, Marc Pypaert, Elizabeth A. Jonas and Stephen G. Waxman^*,¶

^* Department of Neurology, Department of Cell Biology, Department of Internal Medicine, and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and ^¶ Center for Neuroscience and Neuroregeneration Research, Veterans Affairs Connecticut Healthcare, West Haven, CT 06516

Voltage-gated sodium channels expressed on the plasma membrane activate rapidly in response to changes in membrane potential in cells with excitable membranes such as muscle and neurons. Macrophages also require rapid signaling mechanisms as the first line of defense against invasion by microorganisms. In this study, our goal was to examine the role of intracellular voltage-gated sodium channels in macrophage function. We demonstrate that the cardiac voltage-gated sodium channel, NaV1.5, is expressed on the late endosome, but not the plasma membrane, in a human monocytic cell line, THP-1, and primary human monocyte-derived macrophages. Although the neuronal channel, NaV1.6, is also expressed intracellularly, it has a distinct subcellular localization. In primed cells, NaV1.5 regulates phagocytosis and endosomal pH during LPS-mediated endosomal acidification. Activation of the endosomal channel causes sodium efflux and decreased intraendosomal pH. These results demonstrate a functionally relevant intracellular voltage-gated sodium channel and reveal a novel mechanism to regulate macrophage endosomal acidification.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by the National Institutes of Health, the National Multiple Sclerosis Society, a Dana Foundation award in Clinical Hypotheses in Neuroimmunology, and the Bumpus Foundation (to M.D.C.). S.G.W. acknowledges support from the National Multiple Sclerosis Society, Medical Research Service and Rehabilitation Research Service, Department of Veteran Affairs, the Nancy Davis Foundation, and the Center for Neuroscience and Regeneration Research (Paralyzed Veterans of America/United Spinal Association/Yale University).

² Address correspondence and reprint requests to Dr. Michael D. Carrithers, Department of Neurology-LCI-910, Yale University School of Medicine, P.O. Box 208018, New Haven, CT 06520. E-mail address: michael.carrithers{at}yale.edu

³ Abbreviations used in this paper: ClC, electrogenic chloride transporter; DiSBAC₂3, bis-(1,3-diethylthiobarbituric acid) trimethine oxonol; EEA-1, early endosomal Ag-1; LAMP-1, lysosomal-associated membrane protein-1; MOI, multiplicity of infection; NaV1.5 and NaV1.6, voltage-gated sodium channels; SBFI, sodium-binding benzofuran isopthalate; SCN, sodium channel gene designation (SCN5A, NaV1.5) (SCN8A, NaV1.6); TPA, 12-O-tetradecanoylphorbol-13-acetate; TTX, tetrodotoxin.