In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 37 ( 2008-09-16), p. 14064-14069
Abstract:
The three isoforms of PIP5KI (α, β, and γ) synthesize PI4,5P 2 (PIP 2 ) by phosphorylating PI4P. Therefore, it is not clear why platelets, like all eukaryotic cells, have more than one isoform. To test the hypothesis that PIP5KI isoforms have nonoverlapping functions, we generated a murine line containing a null mutation of PIP5KIβ and analyzed the effect on platelet signaling. PIP5KIβ-null mice had normal platelet counts. In contrast to platelets lacking PIP5KIα, platelets lacking PIP5KIβ exhibited impaired aggregation accompanied by disaggregation. Although platelets lacking PIP5KIβ had only a moderate deficiency of PIP 2 under basal conditions, they had a striking deficiency in PIP 2 synthesis and IP 3 formation after thrombin stimulation. We have also observed that platelets lacking both PIP5KIα and PIP5KIβ have a complete loss of thrombin-induced IP 3 synthesis even though they still contain PIP5KIγ, the predominant PIP5KI isoform in platelets. These results demonstrate that PIP5KIβ, like PIP5KIα, contributes to the rapid synthesis of a pool of PIP 2 that is required for second-messenger formation, whereas the pool of PIP 2 synthesized by PIP5KIγ does not contribute to this process. Additionally, we found that PIP5KIβ-null platelets failed to form arterial thrombi properly in vivo . Together, these data demonstrate that PIP5KIβ is required for rapid PIP 2 synthesis, second-messenger production, and stable platelet adhesion under shear in vivo . These results also demonstrate that after stimulation of a G protein-coupled receptor, IP 3 is completely derived from a rapidly synthesized discrete pool of PIP 2 synthesized by PIP5KIα and PIP5KIβ.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0804139105
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2008
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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