Molecular mechanisms of retinal ON-bipolar cell signaling

视网膜暴露在超过9个数量级的光强度下，从多云的夜晚到晚上 从森林到雪山边的晴天，再到不同对比度和频率的图像。要优化 在这一整个范围内，视网膜的反应特性随着刺激的变化而变化 在细胞和网络层面，这一过程称为适应。这项拟议研究的长期目标是 解释视网膜双极细胞光反应调节的分子基础。这些 细胞介导光感受器和神经节细胞之间的光反应传递，是关键部位 适应的问题。视杆双极细胞接受视杆感光细胞的光驱动突触输入并驱动视网膜 通过突触输出到所有的无长突细胞。而暗适应的杆状双极电池可以传输单光子 除了在星光下的反应外，它们还能够在温和的背景光中传递对比度变化。这个 在不同的光照条件下优化杆状双极细胞功能的机制尚不清楚。我们的 最近的工作表明，一种新的基于mGlu5的途径平行于初级光反应 通路可能调节双极细胞的反应。此外，我们已经确定了一种钾通道， Kv11.1，它似乎调节暗适应，并可能受丰富的PKCα调控 在杆状双极细胞中表达。 在黑暗中，光感受器将谷氨酸释放到双极细胞的树突上，并减少谷氨酸 对光刺激的反应而释放。ON-双极细胞的光反应是由一种独特的信号- 双极细胞树突状细胞中G蛋白偶联受体mGlu6启动的逆转途径。在黑暗中， 紧张性激活mGlu6通路使TRPM1阳离子通道处于关闭状态。作为对.的回应 在光刺激下，mGlu6被失活，允许TRPM1通道打开并使细胞去极化。MGlu6- TRPM1途径在所有脊椎动物中都是保守的，mGlu6和TRPM1的突变导致先天性 人类和小鼠模型的静止性夜盲(CSNB)。尽管它在视觉上非常重要， 不同环境下初级兴奋通路调控的分子机制 目前情况仍不得而知。基于与其他系统的类比，以及我们的初步研究，我们 假设mGlu5受体、Kv11.1通道和PKCα调节mGlu6-TRPM1的输出 路径。

The retina is exposed to light intensities that vary over nine orders of magnitude, from a cloudy night in a forest to a sunny day on a snowy mountainside, and to images of varying contrast and frequency. To optimize vision over this entire range, the response properties of the retina change as a function of the stimuli at both the cellular and network level, a process termed adaptation. The long-term goal of the proposed research is to explain the molecular basis for regulation of the light response in retinal ON-bipolar cells. These cells mediate the transmission of light responses between photoreceptors and ganglion cells and are key sites of adaptation. Rod bipolar cells receive light-driven synaptic input from rod photoreceptors and drive retinal output via synapses onto AII amacrine cells. While dark-adapted rod bipolar cells can transmit single photon responses in starlight, they are also able to transmit contrast changes in moderate background light. The mechanisms which optimize rod bipolar cell function under different lighting conditions remain unknown. Our recent work suggests that a novel mGlu5-based pathway operating in parallel to the primary light-response pathway may modulate the ON-bipolar cell responses. Further, we have identified a potassium channel, Kv11.1, that appears to regulate dark adaptation, and may be regulated by PKCα, which is abundantly expressed in rod bipolar cells. In the dark, photoreceptors release glutamate onto dendrites of ON-bipolar cells, and decrease glutamate release in response to light stimuli. The light response of ON-bipolar cells is mediated by a unique, sign- inverting pathway initiated by mGlu6, a G protein-coupled receptor in the ON-bipolar cell dendrites. In the dark, tonic activation of the mGlu6 pathway maintains the TRPM1 cation channel in a closed state. In response to light stimuli, mGlu6 is inactivated, allowing TRPM1 channels to open and depolarize the cell. The mGlu6- TRPM1 pathway is conserved in all vertebrates, and mutations in mGlu6 and TRPM1 cause congenital stationary night blindness (CSNB) in humans and mouse models. Despite its central importance in vision, the molecular mechanisms by which the primary excitatory pathway is modulated under different conditions remain unknown. Based on analogy with other systems, and our Preliminary Studies, we hypothesize that mGlu5 receptors, Kv11.1 channels and PKCα modulate the output of the mGlu6-TRPM1 pathway.