Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1
Shekhar Srivastava,
Saswati Panda,
Zhai Li,
Stephen R Fuhs,
Tony Hunter,
Dennis J Thiele,
Stevan R Hubbard,
Edward Y Skolnik
Affiliations
Shekhar Srivastava
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
Saswati Panda
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
Zhai Li
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
Stephen R Fuhs
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
Dennis J Thiele
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
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
Edward Y Skolnik
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
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.
