title: Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1.
abstract: The calcium activated K(+) channel KCa3.1 plays an important role in T lymphocyte Ca(2+) signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca(2+) influx. We previously showed that nucleoside diphosphate kinase beta (NDPK-B), a mammalian histidine kinase, is required for KCa3.1 channel activation in human CD4 T lymphocytes. We now show that the mammalian protein histidine phosphatase (PHPT-1) directly binds and inhibits KCa3.1 by dephosphorylating histidine 358 on KCa3.1. Overexpression of wild-type, but not a phosphatase dead, PHPT-1 inhibited KCa3.1 channel activity. Decreased expression of PHPT-1 by siRNA in human CD4 T cells resulted in an increase in KCa3.1 channel activity and increased Ca(2+) influx and proliferation after T cell receptor (TCR) activation, indicating that endogenous PHPT-1 functions to negatively regulate CD4 T cells. Our findings provide a previously unrecognized example of a mammalian histidine phosphatase negatively regulating TCR signaling and are one of the few examples of histidine phosphorylation/dephosphorylation influencing a biological process in mammals.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Srivastava
authors.forename: Olga
authors.initials: O
authors.lastname: Zhdanova
authors.forename: Lie
authors.initials: L
authors.lastname: Di
authors.forename: Zhai
authors.initials: Z
authors.lastname: Li
authors.forename: Mamdouh
authors.initials: M
authors.lastname: Albaqumi
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Skolnik
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D015870:Gene Expression; D020868:Gene Silencing; D006639:Histidine / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D034741:RNA, Small Interfering; D006639:Histidine; C504019:PHPT1 protein, human; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium
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