Modulation of cGMP in Retina

视网膜中 cGMP 的调节

基本信息

批准号：
7251433
负责人：
WILLIAM D ELDRED
金额：
$ 35.29万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-08-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7251433
关键词：
6-Cyano-7-nitroquinoxaline-2,3-dione Acetylcholine Address Biochemical Cells Choline O-Acetyltransferase Cholinergic Agents Cholinergic Agonists Confocal Microscopy Cyclic GMP Dopamine Dyes Fluorescence Glutamates Glycine Image Life Light Localized Measures Mediating Methods Movement NMDA receptor antagonist Neurons Neurotransmitters Nicotinic Receptors Nitric Oxide Pathway interactions Peroxonitrite Photons Photoreceptors Physiological Presynaptic Terminals Principal Investigator Process Production Publishing Range Relative (related person)Reporting Retina Retinal Salamander Serotonin Signal Transduction Site Slice Soluble Guanylate Cyclase Source Synapses System Testing Time Tissues Turtles cell type choline transporter cholinergic gamma-Aminobutyric Acid ganglion cell horizontal cell immunocytochemistry neurochemistry neurotransmitter release paraform programs receptor research study response uptake visual stimulus

项目摘要

DESCRIPTION (provided by applicant): The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signal transduction system has physiological functions in every retinal cell type and every retinal cell type can potentially make NO. However, it is not known if visual stimuli modulate NO production in particular cell types. Also, little is known about the underlying synaptic mechanisms, the relative movement or retention of NO from specific cellular sources, and the interactions between NO and other retinal neurotransmitters. This proposal tests four hypotheses: HYPOTHESIS 1- NO production is increased by light through both the ON- and OFF-synaptic pathways. NO imaging indicates many cells can make visually stimulated NO and that both ON- and OFF-synaptic pathways are involved. This will be tested using NO imaging and specific synaptic blockers to anatomically and pharmacologically characterize the cells with visually stimulated NO production. HYPOTHESIS 2- Photoreceptors can release acetylcholine to modulate levels of NO and cGMP in horizontal cells. This will be tested by localizing choline acetyltransferase and nicotinic receptors; using cholinergic agonists to activate NO/cGMP production, and by testing the effects of cholinergic and glutamatergic antagonists on visually stimulated NO/cGMP production. HYPOTHESIS 3 - Nitric oxide is not freely diffusible and there are differences in the retention of nitric oxide produced by different cellular sources. This will be tested using NO imaging, and by using the activation of soluble guanylate cyclase by NO to make cGMP as an independent functional measure of the presence and movement of NO. This will indicate the effective range of NO movement from specific cellular sources and establish precise anatomical limits for interpreting its range of function in retina. HYPOTHESIS 4- NO has reciprocal relationships with GABA, glycine, serotonin, and dopamine, in that NO modulates the release of these neurotransmitters and they in turn can modulate NO production. NO and peroxynitrite can modulate transmitter release by both Ca2+-dependent release systems and by the reversal of Ca2+-independent and Na+-dependent carrier-mediated uptake systems in neurons. Results indicate that NO modulates the neuronal levels of GABA, glycine, and serotonin, and that the selective blocking of GABAergic, glycinergic, and dopaminergic receptors modulates NO/cGMP in retina.

描述（由申请人提供）：一氧化氮（NO）/环状鸟苷单磷酸（CGMP）信号转导系统在每种视网膜细胞类型中都具有生理功能，并且每种视网膜细胞类型都可能无效。但是，尚不清楚视觉刺激是否在特定细胞类型中调节无生产。同样，关于基本的突触机制，特定细胞来源的相对运动或保留以及NO和其他视网膜神经递质之间的相互作用知之甚少。该提案检验了四个假设：假设1-通过在突触外途径和突触外途径中，光线没有产生。没有成像表明许多细胞可以使视觉刺激的否否，并且涉及内和突触的途径。这将使用不使用成像和特定突触阻滞剂进行解剖和药理的特定突触阻滞剂进行测试，以视觉刺激的无产生来表征细胞。假设2-感光体可以释放乙酰胆碱以调节水平细胞中的NO和CGMP水平。这将通过定位胆碱乙酰转移酶和烟碱受体来测试。使用胆碱能激动剂激活NO/CGMP的产生，并通过测试胆碱能和谷氨酸能拮抗剂对视觉刺激的NO/CGMP产生的影响。假设3-一氧化氮不能自由扩散，并且在不同细胞来源产生的一氧化氮的保留率差异。这将使用NO成像进行测试，并通过使用NO将CGMP作为NO的存在和移动的独立功能度量，并使用可溶性鸟苷酸环化酶的激活进行测试。这将表明从特定细胞来源移动的有效范围，并建立精确的解剖限制来解释其在视网膜中的功能范围。假设4- NO与GABA，甘氨酸，5-羟色胺和多巴胺具有相互关系，因为没有调节这些神经递质的释放，而它们反过来又可以调节产生。 NO和过氧亚硝酸盐可以通过Ca2+依赖性释放系统以及Ca2+非依赖性和Na+依赖性的载体介导的神经元中的Ca2+依赖性和Na+依赖性载体介导的摄取系统的反转来调节发射机释放。结果表明，没有调节GABA，甘氨酸和5-羟色胺的神经元水平，并且在视网膜中，GABA能，甘氨酸能和多巴胺能受体的选择性阻断可调节NO/CGMP。