Regulation of photoreceptor neurotransmission.

描述（由申请人提供）：本项目的长期目标是 了解控制视杆和视锥神经传递的机制。 兴奋性神经递质L-谷氨酸从光感受器的释放是 由L型Ca 2+通道的活性调节。在生理电压 在一定范围内，Ca 2+的内流与Ca 2+的内流呈线性关系 通过这些通道和感光器释放谷氨酸 突触这种线性关系不同于最多发现的非线性关系， 其他突触。本申请的一个目的是使用电生理学方法， （电容监测和全细胞膜片钳记录）技术， 笼状Ca ~（2+）的光解和Ca ~（2+）成像技术来检测Ca ~（2+） 依赖于从幼虎蝾螈光感受器释放。一种方式 Ca 2+流入和释放之间可能出现的线性关系是， 囊泡胞吐作用仅由单个Ca 2+离子的结合引发。如果 需要多个Ca 2+离子的结合来启动释放，然后 伊卡和释放之间的线性可能反映线性总和， 伴随着越来越多的Ca 2+通道的激活， 具有非重叠Ca 2+微区的分布式释放位点。这两 可能性将被调查。 大量调制器的存在可以改变电压 光感受器伊卡的依赖性或幅度似乎对 光感受器，以维持稳定水平的伊卡激活所必需的 稳定的突触输出。该应用程序的第二个主要目的是使用 全细胞膜片钳记录以及Ca 2+和Cl-成像技术， 测试三种特定的内在调节因子的相对贡献， 在视杆和视锥光感受器中稳定伊卡激活的机制：（1） Ca依赖性的伊卡失活，（2）突触间隙Ca 2+耗竭，和（3） 激活Ca 2+激活的Cl-通道。除了它们的重要性， 正常视觉，光感受器伊卡调节，细胞内Ca ~（2+） 浓度和谷氨酸释放在脑缺血的病理生理学中也很重要。 视网膜例如，视杆细胞和视锥细胞内Ca 2+水平增加 可能导致光感受器退化和谷氨酸释放增加 由于伊卡的激活增强而引起的兴奋性毒性后果， 突触后神经元因此，了解杆细胞的内在机制， 调节伊卡、细胞内Ca 2+水平和突触传递的视锥细胞 对于了解患病和正常人的生理机能都很重要 视网膜。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the mechanisms that control neurotransmission from rods and cones. Release of the excitatory neurotransmitter L-glutamate from photoreceptors is regulated by the activity of L-type Ca2+ channels. In the physiological voltage range, there appears to be a linear relationship between the influx of Ca2+ through these channels and the release of glutamate at the photoreceptor synapse. This linearity differs from the non-linear relationship found at most other synapses. One aim of this application is to use electrophysiological (capacitance monitoring and whole cell patch clamp recording) techniques, photolysis of caged Ca2+, and Ca2+ imaging techniques to examine the Ca2+ dependence of release from larval tiger salamander photoreceptors. One way in which a linear relationship between Ca2+ influx and release might arise is if vesicular exocytosis is initiated by the binding of only a single Ca2+ ion. If the binding of multiple Ca2+ ions is required to initiate release, then linearity between ICa and release is likely to reflect the linear summation, accompanying activation of an increasing number of Ca2+ channels, of sparsely distributed release sites with non-overlapping Ca2+ microdomains. These two possibilities will be investigated. The existence of a large number of modulators that can alter the voltage dependence or amplitude of photoreceptor ICa appear to present a challenge for photoreceptors to maintain the stable level of ICa activation necessary for stable synaptic output. The second major aim of this application is to use whole cell patch clamp recording as well as Ca2+ and Cl- imaging techniques to test the relative contribution of three specific intrinsic modulatory mechanisms to stabilizing ICa activation in rod and cone photoreceptors: (1) Ca-dependent inactivation of ICa, (2) depletion of synaptic cleft Ca2+, and (3) activation of Ca2+-activated Cl- channels. In addition to their importance in normal vision, regulation of photoreceptor ICa, intracellular Ca2+ concentration, and glutamate release are also important in pathophysiology of the retina. For example, increased intracellular Ca2+ levels in rods and cones may contribute to photoreceptor degeneration, and increased glutamate release arising from enhanced activation of ICa can have excitotoxic consequences on post-synaptic neurons. Thus, understanding the intrinsic mechanisms in rods and cones that regulate ICa, intracellular Ca2+ levels, and synaptic transmission is important for understanding the physiology of both diseased and normal retina.