Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells

  • Mol Cell. 2006 Dec 8;24(5):665-675. doi: 10.1016/j.molcel.2006.11.012.
Shekhar Srivastava  1 ,  Zhai Li  1 ,  Kyung Ko  1 ,  Papiya Choudhury  1 ,  Mamdouh Albaqumi  2 ,  Amanda K Johnson  3 ,  Ying Yan  4 ,  Jonathan M Backer  4 ,  Derya Unutmaz  3 ,  William A Coetzee  5 ,  Edward Y Skolnik  6
Affiliations
  • 1. 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.
  • 2. Division of Nephrology, New York University School of Medicine, New York, New York 10016.
  • 3. Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, Tennessee 37232.
  • 4. Department of Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
  • 5. 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.
  • 6. 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: [email protected].
PMID: 17157250 DOI: 10.1016/j.molcel.2006.11.012
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.