Desensitization of Cone Visual Signaling Pathways

视锥细胞视觉信号通路的脱敏

基本信息

批准号：
8249882
负责人：
Ellen Ruth Weiss
金额：
$ 35.16万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-07 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8249882
关键词：
Adenylate Cyclase Antibodies Arrestins Back Binding Buffers Calcium Calmodulin Cell Cycle Regulation Cell Survival Cell physiology Cell surface Cells Circadian Rhythms Color Visions Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Dark Adaptation Data Defect Development Disease Dopamine Dopamine Agonists Dopamine Antagonists Evaluation Event G protein coupled receptor kinase GRK GRK1 gene GRK7 gene Glutamates Grant In Vitro Incubated Kinetics Knockout Mice Knowledge Lead Light Measures Mediating Metabolism Modeling Mus Mutant Strains Mice Night Blindness Opsin Phospho-Specific Antibodies Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Photoreceptors Phototransduction Play Post-Translational Protein Processing Predisposition Process Protein Dephosphorylation Protein Kinase Proteins Publishing Rattus Recovery Regulation Relative (related person)Retina Retinal Cone Retinal Diseases Rhodopsin Rod Outer Segments Role Second Messenger Systems Series Signal Pathway Signal Transduction Signaling Molecule Simulate Syndrome Testing Time Tissues Transducin Vertebrate Photoreceptors Vision Visual Western Blotting Wild Type Mouse Work base cell type desensitization design dopamine D4 receptor enzyme activity feeding in vivo light intensity loss of function mutation mouse model mutant novel public health relevance response retinal rods rhodopsin kinase second messenger

项目摘要

DESCRIPTION (provided by applicant): Phototransduction in vertebrate rods and cones consists of a series of precisely timed events that are necessary for photoreceptors to function under a broad range of light intensities. While rods operate under dim light and are easily saturated in response to bright light, cones recover more rapidly and are able to adapt to much more intense light. Second messengers, such as cGMP and Ca2+, are already well-known to play important roles in the phototransduction cascade and adaptation in rods and cones. Another second messenger, cAMP, which is regulated both in a light- and a circadian-dependent manner in photoreceptors, may also be important for adaptation. For example, changes in cAMP synthesis are associated with defects in adaptation in rods and cones that alter signaling to the inner retina. Interestingly, phosphorylation of photoreceptor cell proteins by PKA, the downstream target of cAMP, has not been well-studied. We have determined that the retina-specific G protein-coupled receptor kinases, GRK1 and GRK7, which play critical roles in recovery and adaptation in rods and cones, are both substrates for PKA in vitro. We have also shown that phosphorylation by PKA reduces the ability of these kinases to phosphorylate their substrates, the opsins in vitro. In this proposal, we provide new evidence that both kinases are phosphorylated by PKA in vivo and that phosphorylation is regulated by light. We propose to use the mouse as a model to study the functional consequences of GRK1 phosphorylation by PKA on its role in recovery and adaptation. Our data introduce a novel mechanism for the regulation of photoreceptor cell- specific GRKs that may influence multiple facets of phototransduction. PUBLIC HEALTH RELEVANCE: Rods and cones are the cells in the vertebrate retina that mediate our visual response to light. Rods are responsible for dim light vision, whereas cones function in bright light and are responsible for color vision. Significant differences between rods and cones have been observed in the sensitivity and kinetics of the light responses as well as their susceptibility to genetically and environmentally induced disease processes. This proposal is designed to analyze the contributions of GRK1, a kinase that is important in visual signaling in both rods and cones and that has been implicated in disease such as stationary night blindness. These studies are expected to lead to a better understanding of the mechanisms in the retina used to adapt to changing light conditions.

描述（由申请人提供）：脊椎动物杆和锥体中的光转导由一系列精确的定时事件组成，这些事件对于光感受器在广泛的光强度下起作用是必需的。当杆在昏暗的光线下运行，并且响应明亮的光线易于饱和，但圆锥体恢复更快，并且能够适应更强烈的光线。诸如CGMP和CA2+之类的第二使者已经众所周知，在光转导级联和杆上的适应性中起着重要作用。另一个第二信使cAMP在光感受器中以光和昼夜依赖性方式进行调节，也可能对适应很重要。例如，cAMP合成的变化与杆和锥体的适应性缺陷有关，这些缺陷将信号转导向内部视网膜。有趣的是，CAMP的下游靶标PKA对光感受器细胞蛋白的磷酸化尚未得到充分研究。我们已经确定，视网膜特异性G蛋白偶联受体激酶GRK1和GRK7在杆和锥体中的恢复和适应性中起着关键作用，都是PKA体外的底物。我们还表明，PKA磷酸化降低了这些激酶在体外磷酸化其底物的能力。在此提案中，我们提供了新的证据，表明两种激酶均由PKA体内磷酸化，并且磷酸化受光调节。我们建议将小鼠用作模型，以研究PKA在恢复和适应中作用的GRK1磷酸化的功能后果。我们的数据引入了一种新的机制，用于调节感光细胞特异性GRK，这可能会影响光转导的多个方面。公共卫生相关性：杆和锥体是脊椎动物视网膜中介导我们对光的视觉反应的细胞。杆负责昏暗的光视觉，而锥体在明亮的光线下起作用，并负责彩色视觉。在光反应的灵敏度和动力学以及它们对遗传和环境诱导的疾病过程的敏感性中，杆和锥体之间存在显着差异。该建议旨在分析GRK1的贡献，GRK1是一种在杆和锥体中视觉信号中很重要的激酶，并且与诸如固定夜失明等疾病有关。预计这些研究将使人们更好地理解用于适应不断变化的光条件的视网膜机制。