Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells.
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.
Srivastava
Shekhar
S
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.
Li
Zhai
Z
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.
Ko
Kyung
K
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.
Choudhury
Papiya
P
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.
Albaqumi
Mamdouh
M
Division of Nephrology, New York University School of Medicine, New York, New York 10016.
Johnson
Amanda K
AK
Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, Tennessee 37232.
Yan
Ying
Y
Department of Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
Backer
Jonathan M
JM
Department of Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
Unutmaz
Derya
D
Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, Tennessee 37232.
Coetzee
William A
WA
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.
Skolnik
Edward Y
EY
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.
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
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