抑制ORAI1-STIM1-依赖的Ca2+通过调节血小板前凝活性的蛋白激酶C异型的进入
Jinmi Zou1, Pengyu Zhang2, Fiorella A Solari3
1Synapse Research Institute Maastricht, Maastricht, The Netherlands; Department of Biochemistry, CARIM, 6200 MD Maastricht University, Maastricht, The Netherlands.
The Journal of biological chemistry
|October 18, 2024
概括
蛋白激酶C (PKC) 异型通过抑制ORAI1-BIN2-STIM1通路来调节 (Ca2+) 进入血小板,影响血栓形成和血液静止. 这种抑制降低了脂胺暴露和血栓生成.
科学领域:
- 血液学 血液学 血液学
- 细胞生物学 细胞生物学
- 生物化学 生物化学
背景情况:
- 细胞质 (Ca2+) 水平对于血小板功能在血栓形成和血液静止中至关重要.
- ORAI1-STIM1通路是细胞外Ca2+进入人体血小板的关键调节者,特别是在刺激糖蛋白VI (GPVI) 受体后.
研究的目的:
- 调查蛋白激酶C (PKC) 在调节 Ca2+ 通过人类血小板中的 ORAI1-STIM1 途径进入 Ca2+ 的作用.
- 阐明涉及的特定PKC异型及其对血小板激活和凝固的下游影响.
主要方法:
- 从ORAI1或STIM1.1中具有功能丧失突变的患者中使用了血小板.
- 由thapsigargin和GPVI刺激诱导的评估Ca2+进入.
- 使用PKC激活剂和抑制剂,以及蛋白质组分析 (无标签和稳定同位素标签).
- 研究了BIN2和STIM1的酸化,以及功能性血小板测定.
主要成果:
- 萨普西加林诱导的Ca2+进入完全取决于ORAI1-STIM1通路.
- PKC激活显著抑制了GPVI和thapsigargin诱导的Ca2+进入,而不会影响细胞内Ca2+调动.
- 确定了β和βPKC异型在Ca2+进入抑制中的冗余作用.
- 氨酸激酶积极调节GPVI诱导的Ca2+进入和调动.
- 蛋白质组分析揭示了BIN2和STIM1中受调节的化位,PKC异型直接化BIN2和STIM1.
- 通过PKC介导的Ca2+输入的下调导致酸胺暴露和血栓生成的减少.
结论:
- 多个PKC异型体通过ORAI1-BIN2-STIM1复合体作为储存Ca2+进入血小板的负调节剂.
- 这种PKC介导的Ca2+输入抑制在降低血小板依赖凝血的调节中起着重要作用.
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