Phosphatidylinositol 3,4,5-trisphosphate regulates Ca2+ entry via Btk in platelets and megakaryocytes without increasing phospholipase C activity

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Oxford University Press

RESUMO

The role of phosphatidylinositol 3,4,5-trisphosphate (PI3,4,5P3) and Btk in signalling by the collagen receptor glycoprotein VI was investigated. PI3,4,5P3 was increased in platelets from mice deficient in the SH2 domain-containing inositol 5-phosphatase (SHIP), in response to collagen related peptide (CRP). Tyrosine phosphorylation and activation of phospholipase Cγ2 (PLCγ2) were unaltered in SHIP–/– platelets, whereas Btk was heavily tyrosine phosphorylated under basal conditions and maximally phosphorylated by low concentrations of CRP. There was an increase in basal Ca2+, maximal expression of P-selectin, and potentiation of Ca2+ and aminophospholipid exposure to CRP in SHIP–/– platelets in the presence of Ca2+ (1 mM). Microinjection of PI3,4,5P3 into megakaryocytes caused a 3-fold increase in Ca2+ in response to CRP, which was absent in X-linked immunodeficiency (Xid) mice, which have a mutation in the PH domain of Btk. There was a corresponding partial reduction in the sustained level of intracellular Ca2+ in response to CRP in Xid mice but no change in PLC activity. These results demonstrate a novel pathway of Ca2+ entry that involves PI3,4,5P3 and Btk, and which is independent of increased PLC activity.

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