title: Expression of the voltage-gated sodium channel NaV1.5 in the macrophage late endosome regulates endosomal acidification.
abstract: 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.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA. michael.carrithers@yale.edu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Carrithers
authors.forename: Sulayman
authors.initials: S
authors.lastname: Dib-Hajj
authors.forename: Lisette M
authors.initials: LM
authors.lastname: Carrithers
authors.forename: Gouzel
authors.initials: G
authors.lastname: Tokmoulina
authors.forename: Marc
authors.initials: M
authors.lastname: Pypaert
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Jonas
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000143:Acids / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D011992:Endosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000648:ultrastructure; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D010587:Phagocytosis; D010588:Phagosomes / Q000737:chemistry / Q000378:metabolism; D015222:Sodium Channels / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
chemical_list: D000143:Acids; D008070:Lipopolysaccharides; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568320:SCN5A protein, human; C100681:SCN8A protein, human; D015222:Sodium Channels; D013779:Tetrodotoxin; D014701:Veratridine