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Published online
doi:10.1083/jcb.200702050
The Journal of Cell Biology, Vol. 177, No. 2, 317-328
The Rockefeller University Press, 0021-9525 $30.00
© Chung et al.
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Article

Coupling Ca2+ store release to Icrac channel activation in B lymphocytes requires the activity of Lyn and Syk kinases



S. Clare Chung1, Andre Limnander2,3, Tomohiro Kurosaki4,5, Arthur Weiss2,3, and Juan I. Korenbrot1

1 Department of Physiology, 2 Department of Medicine, and 3 Howard Hughes Medical Institute, School of Medicine, University of California, San Francisco, San Francisco, CA 94143
4 Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, and 5 Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Moriguchi 570-8506, Japan

Correspondence to Juan I. Korenbrot: juan.korenbrot{at}ucsf.edu

Activation of the B cell receptor complex in B lymphocytes causes Ca2+ release from intracellular stores, which, in turn, activates ion channels known as Icrac. We investigated the mechanisms that link Ca2+ store release to channel gating in DT40 B lymphocyte cell lines genetically manipulated to suppress the expression of several tyrosine kinases: Btk, Lyn, Syk, and the Blnk adaptor molecule. The simultaneous but not the independent suppression of Lyn and Syk expression prevents the activation of Icrac without interfering with thapsigargin-sensitive Ca2+ store release. Icrac activation by Ca2+ is reversed in mutant cells by the homologous expression of the missing kinases. Pharmacological inhibition of kinase activity by LavendustinA and PP2 cause the same functional deficit as the genetic suppression of enzyme expression. Biochemical assays demonstrate that kinase activity is required as a tonic signal: targets must be phosphorylated to link Ca2+ store release to Icrac gating. The action of kinases on Icrac activation does not arise from control of the expression level of the stromal interaction molecule 1 and Orai1 proteins.

Abbreviations used in this paper: BCR, B cell receptor; IP3, inositol 1,4,5-trisphosphate; STIM1, stromal interaction molecule 1; TG, thapsigargin.


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