Mechanisms of inactivation in Drosophila phototransduction

光感受器通过将光转换成电信号来响应光。这一“光转导”过程涉及一系列生化步骤，每个步骤都涉及一个或多个特定的蛋白质分子(例如视觉色素和催化酶)。最终的结果是被称为“离子通道”的特殊蛋白质的激活，这种蛋白质嵌入细胞周围的膜中。一旦激活，离子通道允许带电离子，如钠和钙，进入细胞，从而产生电信号，这些电信号沿着神经传递到大脑。苍蝇光感受器的非凡之处在于，它能够比脊椎动物眼睛中同等的光感受器快10-100倍的速度产生反应，从而代表着动物界这种生物化学信号传递最快的级联(这是为什么打苍蝇如此困难的主要原因之一)。由于几个原因，果蝇的光传导可以得到特别好的研究。首先，我们现在知道了它的整个遗传密码，并可以操纵它的基因，以便个别基因(从而蛋白质)可以被改变、删除或引入苍蝇体内。其次，我们可以分离苍蝇的光感受器，并使用一种被称为膜片钳的技术以极高的精度记录它们的电信号。第三，我们的实验室开发了专门和复杂的生理学工具，使我们能够监测活的、有反应的细胞中光转导的单个分子步骤的速率。为了快速和可靠地做出反应，光感受器不仅必须对光做出反应，而且还必须能够在光熄灭时终止其活动。虽然光感受器的性能同样重要，但涉及失活的分子步骤却知之甚少。在这项研究计划中，我们将结合我们的生物化学和生理学方法，以及对光转导级联的不同分子成分的遗传操作，以详细了解这些失活机制是如何控制和协调的，以产生这些光感受器的非凡性能。参与产生苍蝇对光的反应的分子并不是苍蝇光感受器所独有的。即使在人类身上，与我们正在研究的分子密切相关的分子也遍布全身。它们在多种过程中发挥着重要作用，如各种激素反应、血压、味觉和嗅觉的调节，以及痛感、冷热感觉。我们从这些研究中获得的知识不仅将让我们详细了解光感受器是如何观看的，而且因为基本的潜在生化机制被广泛发现，将为我们提供对身体中许多其他通常是临床上重要的过程的新见解。

Photoreceptors respond to light by converting it into electrical signals. This process of 'phototransduction' involves a cascade of biochemical steps, each of which involves one or more specific protein molecules (e.g. visual pigments and catalytic enzymes). The end result is the activation of specialised proteins known as 'ion channels', embedded in the membrane surrounding the cell. Once activated, ion channels allow charged ions, such as sodium and calcium, into the cell, thereby generating electrical signals that are transmitted along nerves to the brain. Fly photoreceptors are remarkable in being able to generate responses 10-100 x more rapidly than equivalent photoreceptors in vertebrate eyes thereby representing the fastest biochemical signalling cascade of this sort in the animal kingdom (one of the main reasons why it is so hard to swat a fly!). Phototransduction can be particularly well studied in the fruitfly Drosophila for several reasons. Firstly, we now know its entire genetic code, and can manipulate its genes so that individual genes (and hence proteins) can be altered, deleted or introduced into the fly. Secondly, we can isolate fly photoreceptors and record their electrical signals with extreme precision using a technique known as 'patch-clamp'. Thirdly, our laboratory has developed specialized and sophisticated physiological tools that allow us to monitor the rates of individual molecular steps in phototransduction in living, responding cells. In order to respond quickly and reliably photoreceptors must not only activate in response to light, but must also be able to terminate their activity when the light goes off. Although equally important for photoreceptor performance, the molecular steps involved in inactivation are poorly understood. In this research programme we will combine our biochemical and physiological approaches with genetic manipulation of different molecular components of the phototransduction cascade to provide a detailed understanding of how these inactivation mechanisms are controlled and co-ordinated to generate the remarkable performance of these photoreceptors. The molecules involved in generating the fly's response to light are not unique to fly photoreceptors. Even in humans, molecules closely related to those we are studying are found throughout the body. They play important roles in a wide range of processes such as all manner of hormonal responses, regulation of blood pressure, taste and smell, and sensations of pain, hot and cold. The knowledge we gain from these studies will not only give us a detailed understanding of how photoreceptors see but, because the basic underlying biochemical mechanisms are so widely found, will provide new insight into many other, often clinically important processes in the body.