Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization
Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization
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DOI：
10.1038/35019544
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发表时间：
2000-08-01
影响因子：
21.3
通讯作者：
Logothetis, DE
中科院分区：
文献类型：
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作者：
Kobrinsky, E;Mirshahi, T;Logothetis, DE
磷脂酰肌醇二磷酸(PIP2)直接调节多种功能，如细胞骨架的组织、囊泡运输和离子通道活性。然而，目前尚不清楚PIP2水平的动态变化是否在这些功能中具有生理重要性的调节作用。在这里，我们展示了在天然心肌细胞和异源表达系统中，受体调节的PIP2水解导致GTP结合蛋白刺激的钾电流的脱敏。在质膜上有两条受体调节的通路在这些通道水平上串扰以调制钾电流。一条途径是通过G蛋白的β-伽马亚基发出信号，这些亚基直接与通道结合。Gβγ亚基稳定与PIP2的相互作用，并导致持续的通道激活。第二个途径激活磷脂酶C(PLC)，磷脂酶C水解PIP2，限制Gβ伽马刺激的活性。我们的结果提供了证据，证明PIP2本身是受体调节的第二信使，它的下调解释了一种新的脱敏形式。
Phosphatidylinositol bisphosphate (PIP2) directly regulates functions as diverse as the organization of the cytoskeleton, vesicular transport and ion channel activity. It is not known, however, whether dynamic changes in PIP2 levels have a regulatory role of physiological importance in such functions. Here, we show in both native cardiac cells and heterologous expression systems that receptor-regulated PIP2 hydrolysis results in desensitization of a GTP-binding protein-stimulated potassium current. Two receptor-regulated pathways in the plasma membrane cross-talk at the level of these channels to modulate potassium currents. One pathway signals through the beta gamma subunits of G proteins, which bind directly to the channel. G beta gamma subunits stabilize interactions with PIP2 and lead to persistent channel activation. The second pathway activates phospholipase C (PLC) which hydrolyses PIP2 and limits G beta gamma-stimulated activity. Our results provide evidence that PIP2 itself is a receptor-regulated second messenger, downregulation of which accounts for a new form of desensitization.