ION CHANNELS IN MACULAR MULLER CELLS OF THE HUMAN RETINA

该项目的主要目标是阐明 介导Muller细胞对病理生理条件的反应， 人类视网膜我们的长期目标是了解离子的作用 在调节Muller细胞的反应，以改变在通道 细胞外环境 虽然早期的考虑假设穆勒细胞的生理学是静态的， 我们最近发现，某些钾离子通道，即KIR， 当人类Muller细胞暴露于谷氨酸激动剂时， 在缺血性视网膜中的高浓度，或者凝血酶， 其可随着血-视网膜屏障的破坏而进入视网膜。 这些离子通道的抑制可能是功能性的 因为它们参与钾的体内平衡。 我们还发现，人类黄斑的穆勒细胞可能是 在生理上不同于那些被充分研究的两栖动物视网膜 其中过量的视网膜K+进入米勒细胞的远端部分， 通过它的尾足进入玻璃体。相比之下，我们 电生理学实验表明，黄斑部的尾足 Muller细胞可以从索马和远端区域功能性分离。 然而，我们还发现，黄斑Muller的胞体-终足相互作用， 通过改变这些神经胶质细胞的K+通道活性可以增强细胞的活性。 综上所述，我们的发现提出了细胞外 诱导K+通道活性变化的分子可以调节 体细胞到足尾的通路，用于清除过量的视网膜K+。 同步电生理记录的胞体和尾足 从人类黄斑新鲜分离的Muller细胞将允许直接 细胞外分子对体细胞终足影响的测量 互动根据初步调查结果， 电生理学范例将被用来测试假设， 蛋白激酶C在介导钾通道中起作用 当人Muller细胞暴露于凝血酶时发生的抑制， 谷氨酸激动剂NMDA 了解调节黄斑K+稳态的机制， 帮助我们深入了解视网膜病理学。

The broad objective of this project is to elucidate the mechanisms that mediate Muller cell responses to pathophysiological conditions in the human retina. Our long-range goal is to understand the role of ion channels in regulating the responses of Muller cells to changes in the extracellular environment. While earlier considerations assumed a static physiology for Muller cells, we recently found that certain potassium channels, i.e. KIR, are inhibited when human Muller cells are exposed to an agonist of glutamate, which may be in the high concentrations in the ischemic retina, or to thrombin, which may enter the retina with a breakdown of the blood-retinal barrier. The inhibition of these ion channels is likely to be of functional significance since they are involved in potassium homeostasis. We have also discovered that Muller cells of the human macula may be physiologically different than those of the well-studied amphibian retina in which excess retinal K+ enters the distal parts of the Muller cell and exits via its endfoot into the vitreous. In contrast, our electrophysiological experiments indicate that the endfoot of a macular Muller cell may be functionally isolated from the soma and distal regions. However, we also find that the soma-endfoot interactions in macular Muller cells can be enhanced by altering the K+ channel activity of these glia. Taken together, our findings raise the possibility that extracellular molecules which induce changes in the activity of K+ channels may regulate the soma-to-endfoot pathway for the removal of excess retinal K+. Simultaneous electrophysiological recordings from the somas and endfeet of Muller cells freshly dissociated from the human macula will allow direct measurements of the effects of extracellular molecules on the soma-endfoot interaction. Also, based on preliminary findings, various electrophysiological paradigms will be used to test the hypothesis that protein kinase C plays a role in mediating the potassium channel inhibition that occurs when human Muller cells are exposed to thrombin or the glutamate agonist NMDA. Knowledge of the mechanisms regulating K+ homeostasis in the macula may help us gain insights concerning retinal pathobiology.