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首页> 外文期刊>Cellular Physiology and Biochemistry >Phosphoinositide-dependent kinase PDK1 in the Regulation of Ca~(2+) entry into mast cells
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Phosphoinositide-dependent kinase PDK1 in the Regulation of Ca~(2+) entry into mast cells

机译：磷酸肌醇依赖性激酶PDK1调控Ca〜（2+）进入肥大细胞

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摘要

The function of mast cells is modified by the phosphoinositol-3 (PI3)-kinase pathway. The kinase signals partially through the phosphoinositide-dependent kinase PDK1, which on the one hand activates the serum- and glucocorticoid- inducible kinase SGK1 and on the other hand activates protein kinase PKCδ. SGK1 participates in the stimulation of Ca ~(2+) entry and degranulation, PKCδ inhibits degranulation. The present experiments explored the role of PDK1 in mast cell function. As mice completely lacking PDK1 are not viable, experiments have been performed in mast cells isolated from bone marrow (BMMCs) of PDK1 hypomorphic mice (pdk1 ~(hm)) and their wild-type littermates (pdk1~(wt)). Antigen stimulation via the FcRI receptor was followed by Ca~(2+) entry leading to increase of cytosolic Ca~(2+) activity in pdk1~(wt) BMMCs, an effect significantly blunted in pdk1~(hm) BMMCs. In contrast, Ca ~(2+) release from intracellular stores was not different between BMMCs of the two genotypes. The currents through Ca~(2+)-activated K ~+ channels following antigen exposure were again significantly larger in pdk1~(wt) than in pdk1~(hm) cells. The Ca~(2+) ionophore ionomycin (1 μM) increased the K~+ channel conductance to similar values in both genotypes. β-hexosaminidase and histamine release were similar in pdk1~(wt) BMMCs and pdk1~(hm) BMMCs. PKCδ inhibitor rottlerin increased β-hexosaminidase release in pdk1~(wt) BMMCs but not in pdk1~(hm) BMMCs. Phosphorylation of PKCδ and of the SGK1 target NDRG1, was stimulated by the antigen in pdk1~(wt) but not in pdk1~(hm) cells. The observations reveal a role for PDK1 in the regulation of Ca~(2+) entry into and degranulation of murine mast cells.
机译：肥大细胞的功能被磷酸肌醇3（PI3）激酶途径修饰。该激酶部分通过磷酸肌醇依赖性激酶PDK1发出信号，该激酶一方面激活血清和糖皮质激素诱导的激酶SGK1，另一方面激活蛋白激酶PKCδ。 SGK1参与Ca〜（2+）的进入和脱粒的刺激，PKCδ抑制脱粒。本实验探索了PDK1在肥大细胞功能中的作用。由于完全缺乏PDK1的小鼠是不可行的，因此已经在从PDK1亚型小鼠（pdk1〜（hm））及其野生型同窝小鼠（pdk1〜（wt））的骨髓（BMMC）分离的肥大细胞中进行了实验。经由FcRI受体的抗原刺激之后，Ca〜（2+）进入导致pdk1〜（wt）BMMC中胞质Ca〜（2+）活性增加，这种作用在pdk1〜（hm）BMMC中明显减弱。相反，两种基因型的BMMC之间从细胞内存储释放的Ca〜（2+）并无差异。抗原暴露后，通过Ca〜（2+）激活的K〜+通道的电流在pdk1〜（wt）中再次明显大于pdk1〜（hm）细胞。 Ca〜（2+）离子载体离子霉素（1μM）使两种基因型的K〜+通道电导率增加至相似值。在pdk1〜（wt）BMMCs和pdk1〜（hm）BMMCs中，β-己糖胺酶和组胺的释放相似。 PKCδ抑制剂rottlerin增加pdk1〜（wt）BMMC中β-己糖胺酶的释放，但不增加pdk1〜（hm）BMMC中的β-己糖胺酶的释放。 pdk1〜（wt）细胞中的抗原刺激了PKCδ和SGK1靶NDRG1的磷酸化，而pdk1〜（hm）细胞中的抗原则没有。这些发现揭示了PDK1在调节Ca〜（2+）进入鼠肥大细胞和使其脱粒中的作用。

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