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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

A Corrigendum to this article was published on 01 July 2007

This article has been updated

Abstract

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.

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Figure 1: Development of Itpkb−/− B lymphocytes.
Figure 2: B lymphocyte–autonomous defects in Itpkb−/− mice.
Figure 3: Itpkb−/− B lymphocytes show diminished BCR-mediated proliferation and activation.
Figure 4: Impaired T cell–independent antibody responses to TNP-Ficoll immunization in Itpkb−/− mice.
Figure 5: Normal activation of BCR signaling pathways but enhanced Ca2+ influx in Itpkb−/− B lymphocytes.
Figure 6: Ins(1,3,4,5)P4 inhibits the entry of SOC in B lymphocytes.

Change history

  • 24 May 2007

    In the version of this article initially published, two labels in the key to Figure 6c are reversed. The blue line is “Ins(1,3,4,5)P4 (300 μM)” and the green line is “Ins(1,4,5,6)P4 (300 μM).” The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank C. Trussell, D. Li and S. Zaharevitz for technical assistance, and R. Glynne, B. Wen and C. Schemdt for discussions.

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Correspondence to Michael P Cooke.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Itpkb protein expression. (PDF 562 kb)

Supplementary Fig. 2

Impaired BCR-induced cell cycle progression in Itpkb−/− B lymphocytes. (PDF 577 kb)

Supplementary Fig. 3

Serum Ig quantities. (PDF 1590 kb)

Supplementary Fig. 4

Reduced BCR-stimulated PLC-γ2 activation in Itpkb−/− B lymphocytes. (PDF 560 kb)

Supplementary Fig. 5

Elevated Ca2+ entry in immature and mature in Itpkb−/− B lymphocytes. (PDF 2157 kb)

Supplementary Fig. 6

IP4 inhibits SOC channel activity but does not alter membrane potential. (PDF 557 kb)

Supplementary Fig. 7

Itpkb regulates calcium homeostasis and B lymphocyte fate selection. (PDF 1538 kb)

Supplementary Table 1

Total number of splenic B cell subsets. (PDF 1392 kb)

Supplementary Methods (PDF 72 kb)

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Miller, A., Sandberg, M., Huang, Y. et al. 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. Nat Immunol 8, 514–521 (2007). https://doi.org/10.1038/ni1458

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