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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：
8448724
负责人：
Ellen Ruth Weiss
金额：
$ 33.4万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448724
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.

描述（由申请人提供）：脊椎动物视杆细胞和视锥细胞中的光转导由一系列精确定时的事件组成，这些事件是光感受器在宽范围的光强度下发挥功能所必需的。视杆细胞在昏暗的光线下工作，并且很容易对明亮的光线做出饱和反应，而视锥细胞恢复得更快，能够适应更强烈的光线。第二信使，如cGMP和Ca2+，已经众所周知，在杆和锥细胞的光转导级联和适应中发挥重要作用。另一种第二信使cAMP在光感受器中以光依赖性和昼夜节律依赖性的方式进行调节，这可能对适应也很重要。例如，cAMP合成的变化与杆和锥中的适应缺陷有关，这些缺陷改变了对内层视网膜的信号传导。有趣的是，PKA（cAMP的下游靶点）对感光细胞蛋白的磷酸化作用尚未得到充分研究。我们已经确定，视网膜特异性G蛋白偶联受体激酶，GRK1和GRK7，这在恢复和适应杆和锥中发挥关键作用，都是PKA在体外的底物。我们还表明，PKA的磷酸化降低了这些激酶磷酸化其底物的能力，视蛋白在体外。在这个建议中，我们提供了新的证据，这两种激酶在体内被PKA磷酸化，磷酸化受光的调节。我们建议使用小鼠作为模型来研究GRK1磷酸化PKA在恢复和适应中的作用的功能后果。我们的数据介绍了一种新的机制，调节感光细胞特异性GRKs，可能会影响多方面的光转导。