Inhibitory modulation of B cell receptor-mediated Ca2+ mobilization by Src homology 2 domain-containing inositol 5'-phosphatase (SHIP).
Src homology 2 domain-containing inositol 5'-phosphatase (SHIP) mediates inhibitory signals that attenuate intracellular Ca2+ mobilization in B cells upon B cell receptor (BCR) stimulation. To clarify the mechanisms affected by SHIP, we analyzed Ca2+ mobilization in the DT40 B cell line in which the SHIP gene was disrupted. In SHIP-deficient cells, Ca2+ transient elicited by BCR stimulation was more prolonged than that in control cells both in the presence and absence of extracellular Ca2+. Inositol 1,4, 5-trisphosphate production following BCR stimulation was enhanced in SHIP-deficient cells. In SHIP-deficient cells in comparison with the control cells, BCR stimulation in the absence of extracellular Ca2+ induced a greater degree of Ca2+ store depletion and the Ca2+ influx upon re-addition of extracellular Ca2+ was also greater. However, store-operated Ca2+ influx (SOC) elicited by thapsigargin-induced store depletion was not affected by SHIP. These results indicate that the primary target pathway of SHIP is the Ca2+ release from the stores, and that Ca2+ influx by the SOC mechanism is secondarily controlled by the level of Ca2+ in the stores without direct inhibition of SOC. In this way, SHIP may play an important role in ensuring the robust tuning of Ca2+ signaling in B cells.
Hashimoto
A
A
Department of Pharmacology, Faculty of Medicine, University of Tokyo, and CREST, Japan Science and Technology Corporation, Tokyo 113, Japan.
Hirose
K
K
Okada
H
H
Kurosaki
T
T
Iino
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology; D019284:Thapsigargin / Q000494:pharmacology; D018909:src Homology Domains
D011947:Receptors, Antigen, B-Cell; D019284:Thapsigargin; D015544:Inositol 1,4,5-Trisphosphate; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D002118:Calcium