Wu Li, Bauer Claudia S, Zhen Xiao-guang, Xie Cheng, Yang Jian
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Nature. 2002 Oct 31;419(6910):947-52. doi: 10.1038/nature01118.
Voltage-gated calcium channels (VGCCs) conduct calcium into cells after membrane depolarization and are vital for diverse biological events. They are regulated by various signalling pathways, which has profound functional consequences. The activity of VGCCs decreases with time in whole-cell and inside-out patch-clamp recordings. This rundown reflects persistent intrinsic modulation of VGCCs in intact cells. Although several mechanisms have been reported to contribute to rundown of L-type channels, the mechanism of rundown of other types of VGCC is poorly understood. Here we show that phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), an essential regulator of ion channels and transporters, is crucial for maintaining the activity of P/Q- and N-type channels. Activation of membrane receptors that stimulate hydrolysis of PtdIns(4,5)P2 causes channel inhibition in oocytes and neurons. PtdIns(4,5)P2 also inhibits P/Q-type channels by altering the voltage dependence of channel activation and making the channels more difficult to open. This inhibition is alleviated by phosphorylation by protein kinase A. The dual actions of PtdIns(4,5)P2 and the crosstalk between PtdIns(4,5)P2 and protein kinase A set up a dynamic mechanism through which the activity of VGCCs can be finely tuned by various neurotransmitters, hormones and trophic factors.
电压门控性钙通道（VGCCs）在细胞膜去极化后将钙离子导入细胞内，对多种生物学事件至关重要。它们受多种信号通路调控，具有深远的功能影响。在全细胞和内面向外膜片钳记录中，VGCCs的活性会随时间降低。这种衰减反映了完整细胞中VGCCs持续的内在调节。尽管已有多种机制被报道与L型通道的衰减有关，但其他类型VGCC衰减的机制仍知之甚少。在此我们表明，磷脂酰肌醇-4,5-二磷酸（PtdIns(4,5)P2），一种离子通道和转运体的重要调节因子，对于维持P/Q型和N型通道的活性至关重要。刺激PtdIns(4,5)P2水解的膜受体激活会导致卵母细胞和神经元中的通道抑制。PtdIns(4,5)P2还通过改变通道激活的电压依赖性并使通道更难打开来抑制P/Q型通道。蛋白激酶A的磷酸化可减轻这种抑制。PtdIns(4,5)P2的双重作用以及PtdIns(4,5)P2与蛋白激酶A之间的相互作用建立了一种动态机制，通过该机制，VGCCs的活性可被多种神经递质、激素和营养因子精确调节。
