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)P-3) 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)P-3 3-kinase B (Itpkb), which converts Ins( 1,4,5) P-3 to inositol-1,3,4,5-tetrakisphosphate (Ins( 1,3,4,5)P-4), 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) P-4. Our data identify Itpkb and its product Ins( 1,3,4,5) P-4 as inhibitors of store-operated Ca2+ channels and crucial regulators of B cell selection and activation.