cGMP and Photoreceptor Function

cGMP 和光感受器功能

• 批准号: 7219497
• 负责人: Rick H Cote
• 金额: $ 32.97万
• 依托单位: UNIVERSITY OF NEW HAMPSHIRE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219497
• 关键词: A 17; Accounting; Active Sites; Adverse effects; Affinity; Allosteric Regulation; Animals; Binding; Binding Proteins; Biochemical; Biological Assay; Blindness; Catalytic Domain; Cells; Cyclic GMP; Detection; Disease susceptibility; Disruption; Drug Delivery Systems; Enzymes; Event; FGF9 gene; Family; Functional disorder; Future; Gene Mutation; Genetic; Glutamic Acid; Goals; Holoenzymes; Human; Hydrolysis; In Vitro; Indium; Kinetics; Lead; Leber' s disease; Light; Light Adaptations; Measures; Metabolic Pathway; Molecular; Mutation; Night Blindness; Noise; PDE2 phosphodiesterase; Pathway interactions; Pharmaceutical Preparations; Phosphodiesterase Inhibitors; Photons; Photoreceptors; Phototransduction; Proteins; RNA Splicing; Regulation; Relative (related person); Reporting; Research; Research Personnel; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Role; Structure; Testing; Therapeutic; Transducin; Variant; Vertebrate Photoreceptors; Vision; Visual; Visual Pathways; Work; base; design; gametocyte activating factor; human disease; intracellular protein transport; novel; peripherin; phosphoric diester hydrolase; prenyl; programs; protein transport; response; retinal rods; visual excitation

DESCRIPTION (provided by applicant): Precise regulation of cyclic GMP (cGMP) levels is required for the initial events of vision in the photoreceptor cells of the retina. Disruptions in the cGMP metabolic pathway, whether resulting from genetic mutations or from therapeutic drug treatments, can cause impaired vision and/or retinal disease (e.g., retinitis pigmentosa, congenital stationary night-blindness) in humans and in animals. While major advances have been made in understanding the molecular basis of visual transduction in rod photoreceptors, there remain important unanswered questions about how the central enzyme of visual excitation, cGMP phosphodiesterase (PDE6), is activated and regulated. Furthermore, two photoreceptor proteins, the glutamic acid-rich protein-2 (GARP2) and the 17 kDa prenyl binding protein (PrBP/d), interact with PDE6 but their functions during phototransduction remain unknown. The specific aims of the research are to: 1. Determine how allosteric regulation of PDE6 by cGMP binding and by its inhibitory Pgamma subunit influence the magnitude and lifetime of transducin activation of PDE6. 2. Test the hypothesis that the glutamic acid-rich protein-2 (GARP2) regulates the catalytic activity of PDE6 in rod photoreceptors. 3. Define the role of the 17 kDa prenyl binding protein (PrBP/d) in the transport and regulation of PDE6 and other prenylated proteins in photoreceptor cells. Mutations in PDE6 subunits, as well as in proteins known to interact with GARP2 or PrBP/d, can cause retinal disease. With the increasing use of phosphodiesterase inhibitors to treat human diseases, the susceptibility of PDE6 to inhibition by these drugs is a concern. Understanding PDE6 regulation at the molecular level is critical for designing effective therapies for certain forms of retinal degeneration, and to better avoid adverse side effects from the use of phosphodiesterase inhibitors as therapeutic drugs. The central enzyme in the visual pathway of rods and cones is the photoreceptor phosphodiesterase (PDE6). Genetic mutations in this protein can lead to loss of visual function, retinal disease, and/or total blindness. With the recent upsurge in the use of phosphodiesterase inhibitors as treatments for a variety of human diseases, adverse effects on vision due to PDE6 inhibition must be considered. Understanding PDE6 at the molecular level is crucial for future efforts to cure certain forms of retinal disease, as well as in avoiding harmful side effects of therapeutic drugs targeting phosphodiesterases for other human diseases.

描述（由申请人提供）：在视网膜的光感受器细胞中，必须精确调控环状GMP（CGMP）水平。 CGMP代谢途径的破坏，无论是遗传突变还是由治疗药物治疗引起的，都会导致人类和动物中的视力和/或视网膜疾病（例如，色素性视网膜炎，先天性夜行）和/或动物中。尽管在理解Rod感光体视觉转导的分子基础方面取得了重大进展，但有关视觉激发中心酶CGMP磷酸二酯酶（PDE6）如何被激活和调节仍然存在重要的未解决问题。此外，两种感光蛋白，富含谷氨酸的蛋白-2（GARP2）和17 kDa的蛋白质结合蛋白（PRBP/d）与PDE6相互作用，但是它们在光转传过程中的功能仍然未知。 研究的具体目的是： 1。确定CGMP结合及其抑制性PGAMMA亚基对PDE6的变构调节如何影响PDE6的跨核素激活的幅度和寿命。 2。检验以下假设：富含谷氨酸的蛋白-2（GARP2）调节PDE6在杆感光体中的催化活性。 3。定义17 kDa前结合蛋白（PRBP/d）在光感受器细胞中PDE6和其他原始化蛋白的运输和调节中的作用。 PDE6亚基中的突变以及已知与GARP2或PRBP/D相互作用的蛋白质可能引起视网膜疾病。随着磷酸二酯酶抑制剂对治疗人类疾病的越来越多，PDE6对这些药物抑制的敏感性是一个问题。了解分子水平的PDE6调节对于设计某些形式的视网膜变性的有效疗法至关重要，并且可以更好地避免使用使用磷酸二酯酶抑制剂作为治疗药物的不利副作用。 杆和锥形视觉途径中的中心酶是感光磷酸二酯酶（PDE6）。该蛋白质中的遗传突变会导致视觉功能，视网膜疾病和/或完全失明的丧失。随着最近在使用磷酸二酯酶抑制剂作为多种人类疾病的治疗方法中的高潮，必须考虑对PDE6抑制引起的视力不利影响。在分子水平上了解PDE6对于未来治愈某些形式的视网膜疾病以及避免针对其他人类疾病的治疗药物的有害副作用至关重要。