title: Disruption of kv1.3 channel forward vesicular trafficking by hypoxia in human T lymphocytes.
abstract: Hypoxia in solid tumors contributes to decreased immunosurveillance via down-regulation of Kv1.3 channels in T lymphocytes and associated T cell function inhibition. However, the mechanisms responsible for Kv1.3 down-regulation are not understood. We hypothesized that chronic hypoxia reduces Kv1.3 surface expression via alterations in membrane trafficking. Chronic hypoxia decreased Kv1.3 surface expression and current density in Jurkat T cells. Inhibition of either protein synthesis or degradation and endocytosis did not prevent this effect. Instead, blockade of clathrin-coated vesicle formation and forward trafficking prevented the Kv1.3 surface expression decrease in hypoxia. Confocal microscopy revealed an increased retention of Kv1.3 in the trans-Golgi during hypoxia. Expression of adaptor protein-1 (AP1), responsible for clathrin-coated vesicle formation at the trans-Golgi, was selectively down-regulated by hypoxia. Furthermore, AP1 down-regulation increased Kv1.3 retention in the trans-Golgi and reduced Kv1.3 currents. Our results indicate that hypoxia disrupts AP1/clathrin-mediated forward trafficking of Kv1.3 from the trans-Golgi to the plasma membrane thus contributing to decreased Kv1.3 surface expression in T lymphocytes.
authors.affiliation: Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA.
authors.forename: Ameet A
authors.initials: AA
authors.lastname: Chimote
authors.forename: Zerrin
authors.initials: Z
authors.lastname: Kuras
authors.forename: Laura
authors.initials: L
authors.lastname: Conforti
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology; D022163:Clathrin-Coated Vesicles / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000096:biosynthesis* / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D021601:trans-Golgi Network / Q000235:genetics / Q000378:metabolism
chemical_list: D051664:Kv1.3 Potassium Channel; D018808:Transcription Factor AP-1