title: Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells.
abstract: The Ca2+ -activated K+ channel KCa3.1 is required for Ca2+ influx and the subsequent activation of B and T cells. Inhibitors of KCa3.1 are in development to treat autoimmune diseases and transplant rejection, underscoring the importance in understanding how these channels are regulated. We show that nucleoside diphosphate kinase B (NDPK-B), a mammalian histidine kinase, functions downstream of PI(3)P to activate KCa3.1. NDPK-B directly binds and activates KCa3.1 by phosphorylating histidine 358 in the carboxyl terminus of KCa3.1. Endogenous NDPK-B is also critical for KCa3.1 channel activity and the subsequent activation of CD4 T cells. These findings provide one of the best examples whereby histidine phosphorylation regulates a biological process in mammals, and provide an example whereby a channel is regulated by histidine phosphorylation. The critical role for NDPK-B in the reactivation of CD4 T cells indicates that understanding NDPK-B regulation should uncover novel pathways required for T cell activation.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016; The Skirball Institute, New York University School of Medicine, New York, New York 10016.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016; The Skirball Institute, New York University School of Medicine, New York, New York 10016.
authors.forename: Zhai
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016; The Skirball Institute, New York University School of Medicine, New York, New York 10016.
authors.forename: Kyung
authors.initials: K
authors.lastname: Ko
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016; The Skirball Institute, New York University School of Medicine, New York, New York 10016.
authors.forename: Papiya
authors.initials: P
authors.lastname: Choudhury
authors.affiliation: Division of Nephrology, New York University School of Medicine, New York, New York 10016.
authors.forename: Mamdouh
authors.initials: M
authors.lastname: Albaqumi
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, Tennessee 37232.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Backer
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, Tennessee 37232.
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016; Pediatric Cardiology, New York University School of Medicine, New York, New York 10016.
authors.forename: William A
authors.initials: WA
authors.lastname: Coetzee
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York 10016; Division of Nephrology, New York University School of Medicine, New York, New York 10016; The Skirball Institute, New York University School of Medicine, New York, New York 10016. Electronic address: skolnik@saturn.med.nyu.edu.
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Skolnik
mesh_terms: D000595:Amino Acid Sequence; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D006639:Histidine / Q000378:metabolism*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology; D008969:Molecular Sequence Data; D054778:NM23 Nucleoside Diphosphate Kinases; D009701:Nucleoside-Diphosphate Kinase / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D013997:Time Factors; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D054778:NM23 Nucleoside Diphosphate Kinases; D006639:Histidine; C517940:NME2 protein, human; D009701:Nucleoside-Diphosphate Kinase; D000077191:Wortmannin