title: Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1.
abstract: KCa2.1, KCa2.2, KCa2.3 and KCa3.1 constitute a family of mammalian small- to intermediate-conductance potassium channels that are activated by calcium-calmodulin. KCa3.1 is unique among these four channels in that activation requires, in addition to calcium, phosphorylation of a single histidine residue (His358) in the cytoplasmic region, by nucleoside diphosphate kinase-B (NDPK-B). The mechanism by which KCa3.1 is activated by histidine phosphorylation is unknown. Histidine phosphorylation is well characterized in prokaryotes but poorly understood in eukaryotes. Here, we demonstrate that phosphorylation of His358 activates KCa3.1 by antagonizing copper-mediated inhibition of the channel. Furthermore, we show that activated CD4(+) T cells deficient in intracellular copper exhibit increased KCa3.1 histidine phosphorylation and channel activity, leading to increased calcium flux and cytokine production. These findings reveal a novel regulatory mechanism for a mammalian potassium channel and for T-cell activation, and highlight a unique feature of histidine versus serine/threonine and tyrosine as a regulatory phosphorylation site.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States.|Division of Nephrology, New York University School of Medicine, New York, United States.|Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University, New York, United States.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States.|Division of Nephrology, New York University School of Medicine, New York, United States.|Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University, New York, United States.
authors.forename: Saswati
authors.initials: S
authors.lastname: Panda
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States.|Division of Nephrology, New York University School of Medicine, New York, United States.|Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University, New York, United States.
authors.forename: Zhai
authors.initials: Z
authors.lastname: Li
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Fuhs
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Tony
authors.identifier: 0000-0002-7691-6993
authors.initials: T
authors.lastname: Hunter
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States.|Department of Biochemistry, Duke University School of Medicine, Durham, United States.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Thiele
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States.|Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University, New York, United States.
authors.forename: Stevan R
authors.identifier: 0000-0002-2707-9383
authors.initials: SR
authors.lastname: Hubbard
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States.|Division of Nephrology, New York University School of Medicine, New York, United States.|Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University, New York, United States.
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Skolnik
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006639:Histidine / Q000378:metabolism*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D006639:Histidine; D003300:Copper; D009701:Nucleoside-Diphosphate Kinase; C542596:NDPK-B protein, human
keywords: cell biology; copper inhibition; histidine phosphorylation; none; potassium channel