Band-pass processing in a GPCR signaling pathway selects for NFAT transcription factor activation.
Band-pass processing in a GPCR signaling pathway selects for NFAT transcription factor activation.
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GPCR 信号通路中的带通处理选择 NFAT 转录因子激活。
DOI：
10.1039/c5ib00181a
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Linderman,JJ
中科院分区：
文献类型：
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作者：
Sumit,M;Neubig,RR;Takayama,S;Linderman,JJ
许多生物过程都是有节奏的，适当的时间越来越被认为是发展和维持生理功能的关键。为了了解输入信号的时间调制如何影响下游反应，我们采用微流控脉冲刺激的G-蛋白偶联受体，毒蕈碱M3受体，在单细胞中同时实时成像的细胞内钙离子和NFAT核定位。有趣的是，我们发现，减少刺激与配体的脉冲可以提供更有效的转录因子激活，如果刺激是适当的时间。我们的实验和计算分析表明，M3受体诱导的钙振荡形成一个低通滤波器，而钙诱导的NFAT易位形成一个高通滤波器。该组合充当针对刺激的中间频率优化的带通滤波器。我们表明，受体脱敏和NFAT易位率确定的带通滤波器的关键功能，带通可能会转移不同的受体或NFAT动态。作为一个例子，我们表明，这两个NFAT亚型（NFAT 4和NFAT 1）已移动带通窗口相同的受体。虽然我们特别关注M3毒蕈碱受体和NFAT易位，但带通处理预计将成为适用于多种信号传导途径的一般主题。
Many biological processes are rhythmic and proper timing is increasingly appreciated as being critical for development and maintenance of physiological functions. To understand how temporal modulation of an input signal influences downstream responses, we employ microfluidic pulsatile stimulation of a G-protein coupled receptor, the muscarinic M3receptor, in single cells with simultaneous real-time imaging of both intracellular calcium and NFAT nuclear localization. Interestingly, we find that reduced stimulation with pulses of ligand can give more efficient transcription factor activation, if stimuli are timed appropriately. Our experiments and computational analyses show that M3receptor-induced calcium oscillations form a low pass filter while calcium-induced NFAT translocation forms a high pass filter. The combination acts as a band-pass filter optimized for intermediate frequencies of stimulation. We demonstrate that receptor desensitization and NFAT translocation rates determine critical features of the band-pass filter and that the band-pass may be shifted for different receptors or NFAT dynamics. As an example, we show that the two NFAT isoforms (NFAT4 and NFAT1) have shifted band-pass windows for the same receptor. While we focus specifically on the M3muscarinic receptor and NFAT translocation, band-pass processing is expected to be a general theme that applies to multiple signaling pathways.