Kobrinsky E, Mirshahi T, Zhang H, Jin T, Logothetis D E
Department of Physiology & Biophysics, Mount Sinai School of Medicine of the New York University, New York, New York 10029, USA.
Nat Cell Biol. 2000 Aug;2(8):507-14. doi: 10.1038/35019544.
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 betagamma subunits of G proteins, which bind directly to the channel. Gbetagamma subunits stabilize interactions with PIP2 and lead to persistent channel activation. The second pathway activates phospholipase C (PLC) which hydrolyses PIP2 and limits Gbetagamma-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.
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，PIP2水平的动态变化在这些功能中是否具有生理重要性的调节作用尚不清楚。在这里，我们在天然心肌细胞和异源表达系统中均表明，受体调节的PIP2水解导致GTP结合蛋白刺激的钾电流脱敏。质膜中的两条受体调节途径在这些通道水平上相互作用以调节钾电流。一条途径通过G蛋白的βγ亚基发出信号，该亚基直接与通道结合。Gβγ亚基稳定与PIP2的相互作用并导致通道持续激活。第二条途径激活磷脂酶C（PLC），其水解PIP2并限制Gβγ刺激的活性。我们的结果提供了证据，表明PIP2本身是一种受体调节的第二信使，其下调导致了一种新的脱敏形式。
