Production of Ins(1,3,4,5)P4 mediated by the kinase Itpkb inhibits store-operated calcium channels and regulates B cell selection and activation.
Antigen receptor-mediated production of inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) in lymphocytes triggers the release of Ca2+ from intracellular stores; this release of Ca2+ results in the opening of store-operated Ca2+ channels in the plasma membrane. Here we report that mice lacking Ins(1,4,5)P3 3-kinase B (Itpkb), which converts Ins(1,4,5)P3 to inositol-1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), had impaired B lymphocyte development and defective immunoglobulin G3 antibody responses to a T lymphocyte-independent antigen. Itpkb-deficient B lymphocytes had the phenotypic and functional features of tolerant B lymphocytes and showed enhanced activity of store-operated Ca2+ channels after B lymphocyte receptor stimulation, which was reversed by the provision of exogenous Ins(1,3,4,5)P4. Our data identify Itpkb and its product Ins(1,3,4,5)P4 as inhibitors of store-operated Ca2+ channels and crucial regulators of B cell selection and activation.
Miller
Andrew T
AT
The Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
Sandberg
Mark
M
Huang
Yina H
YH
Young
Michael
M
Sutton
Susan
S
Sauer
Karsten
K
Cooke
Michael P
MP
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D007295:Inositol Phosphates / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*
D015220:Calcium Channels; D007295:Inositol Phosphates; C081655:inositol-1,3,4,5-tetrakisphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D002118:Calcium