Timing Is Everything: GTPase Regulation in Phototransduction
Timing Is Everything: GTPase Regulation in Phototransduction
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DOI：
10.1167/iovs.13-13281
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发表时间：
2013-11-01
影响因子：
4.4
通讯作者：
Wensel, Theodore G.
中科院分区：
文献类型：
--
作者：
Arshavsky, Vadim Y.;Wensel, Theodore G.
随着脊椎动物光导的分子机制在20世纪80年代变得越来越清晰，一个持续存在的问题是由光导G蛋白、转导蛋白催化的GTP缓慢水解与光感受器细胞从光刺激中更快的生理恢复之间的差异。从1989年发表的一份报告开始，一系列研究表明，转导蛋白GTPase活性可以接近解释存在于杆外段膜中的一种或多种因素的生理恢复动力学所需的速率。这些因子一个接一个地被确定，从PDEc开始，由转导蛋白激活的cGMP磷酸二酯酶的抑制亚基。随后发现了G蛋白信号的调节因子RGS9所起的关键作用，RGS9是一个普遍存在的gtpase加速蛋白家族的成员，或称为gap，用于异源三聚体G蛋白。不久之后，G蛋白β异构体G β 5被确定为专性伴侣亚基，随后发现了R9AP，一种跨膜蛋白，将RGS9 GAP复合物固定在盘膜上，对该复合物在体内的定位、稳定性和活性至关重要。首先通过敲除小鼠模型明确了该复合体所有成员的生理重要性，然后通过发现一种人类视觉缺陷——弱视，这是由一种GAP成分的遗传缺陷引起的。通过亚络合物的高分辨率晶体结构，以及在体外和动物模型中进行的广泛的机制研究，已经获得了进一步的见解。
As the molecular mechanisms of vertebrate phototransduction became increasingly clear in the 1980s, a persistent problem was the discrepancy between the slow GTP hydrolysis catalyzed by the phototransduction G protein, transducin, and the much more rapid physiological recovery of photoreceptor cells from light stimuli. Beginning with a report published in 1989, a series of studies revealed that transducin GTPase activity could approach the rate needed to explain physiological recovery kinetics in the presence of one or more factors present in rod outer segment membranes. One by one, these factors were identified, beginning with PDEc, the inhibitory subunit of the cGMP phosphodiesterase activated by transducin. There followed the discovery of the crucial role played by the regulator of G protein signaling, RGS9, a member of a ubiquitous family of GTPase-accelerating proteins, or GAPs, for heterotrimeric G proteins. Soon after, the G protein beta isoform G beta 5 was identified as an obligate partner subunit, followed by the discovery or R9AP, a transmembrane protein that anchors the RGS9 GAP complex to the disk membrane, and is essential for the localization, stability, and activity of this complex in vivo. The physiological importance of all of the members of this complex was made clear first by knockout mouse models, and then by the discovery of a human visual defect, bradyopsia, caused by an inherited deficiency in one of the GAP components. Further insights have been gained by high-resolution crystal structures of subcomplexes, and by extensive mechanistic studies both in vitro and in animal models.