PDF(Pubmed)
Abstract：
Retinal rods evolved to be able to detect single photons. Despite their exquisite sensitivity, rods operate over many log units of light intensity. Several processes inside photoreceptor cells make this incredible light adaptation possible. Here, we added to our previously developed, fully space resolved biophysical model of rod phototransduction, some of the mechanisms that play significant roles in shaping the rod response under high illumination levels: the function of RGS9 in shutting off G protein transducin, and calcium dependences of the phosphorylation rates of activated rhodopsin, of the binding of cGMP to the light-regulated ion channel, and of two membrane guanylate cyclase activities. A well stirred version of this model captured the responses to bright, saturating flashes in WT and mutant mouse rods and was used to explain \"Pepperberg plots,\" that graph the time during which the response is saturated against the natural logarithm of flash strength for bright flashes. At the lower end of the range, saturation time increases linearly with the natural logarithm of flash strength. The slope of the relation (τD) is dictated by the time constant of the rate-limiting (slowest) step in the shutoff of the phototransduction cascade, which is the hydrolysis of GTP by transducin. We characterized mathematically the X-intercept ( Φ o ) which is the number of photoisomerizations that just saturates the rod response. It has been observed that for flash strengths exceeding a few thousand photoisomerizations, the curves depart from linearity. Modeling showed that the \"upward bend\" for very bright flash intensities could be explained by the dynamics of RGS9 complex and further predicted that there would be a plateau at flash strengths giving rise to more than ~107 photoisomerizations due to activation of all available PDE. The model accurately described alterations in saturation behavior of mutant murine rods resulting from transgenic perturbations of the cascade targeting membrane guanylate cyclase activity, and expression levels of GRK, RGS9, and PDE. Experimental results from rods expressing a mutant light-regulated channel purported to lack calmodulin regulation deviated from model predictions, suggesting that there were other factors at play.
摘要：
视网膜棒进化为能够检测单个光子。尽管他们非常敏感，棒在许多日志单位的光强度上运行。感光细胞内部的几个过程使这种令人难以置信的光适应成为可能。这里,我们增加了我们以前开发的，杆光转导的完全空间分辨生物物理模型，在高光照水平下形成杆状反应中起重要作用的一些机制：RGS9在关闭G蛋白转导素方面的功能，和钙依赖性的活化视紫红质的磷酸化率，cGMP与光调节离子通道的结合，和两种膜鸟苷酸环化酶活性。这个模型的一个很好的版本捕捉到了对明亮的反应，WT和突变小鼠杆中的饱和闪烁，用于解释“Pepperberg图”，“该图显示了响应相对于明亮闪光的闪光强度的自然对数饱和的时间。在范围的下端，饱和时间随着闪光强度的自然对数线性增加。关系的斜率（τD）由光传导级联关闭中限速（最慢）步骤的时间常数决定，它是通过转导素水解GTP。我们在数学上表征了X截距（Φo），它是使棒响应饱和的光异构化次数。已经观察到，对于超过几千个光异构化的闪蒸强度，曲线偏离线性。建模表明，对于非常明亮的闪光强度，“向上弯曲”可以通过RGS9复合物的动力学来解释，并进一步预测，由于所有可用的PDE的活化，在闪光强度下会有一个平台，导致超过107个光异构化。该模型准确地描述了由于级联靶向膜鸟苷酸环化酶活性的转基因扰动而导致的突变鼠杆饱和行为的改变，和GRK的表达水平，RGS9和PDE。表达突变光调节通道的杆的实验结果据称缺乏钙调蛋白调节，偏离了模型预测，这表明还有其他因素在起作用。
