DEPRESSION: ATPASE REGULATOR AND NOREPINEPHRINE

抑郁症：ATP酶调节剂和去甲肾上腺素

• 批准号: 3376062
• 负责人: Alan C Swann
• 金额: $ 10.04万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1988-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3376062
• 关键词: adenosinetriphosphatase; antidepressants; autoradiography; brain cell; cardiac glycosides; catecholamines; cyclic AMP; depression; gel electrophoresis; human tissue; ion transport; membrane permeability; neurotransmitter metabolism; norepinephrine; thyroid hormones

The research in this proposal will examine the regulation of (Na+,K+)-ATPase in vivo by norepinephrine and by a specific endogenous inhibitor of the enzyme. (Na+,K+)-ATPase is the enzymatic basis of energy-dependent Na+ and K+ transport and has a central role in the regulation of intracellular cation concentrations and, hence, of membrane potential, cell excitability, and energy utilization. The experiments in this proposal are in four parts. 1) Experiments examining regulation of (Na+,K+)-ATPase, and interactions between norepinephrine and thyroid or adrenocortical hormones in regulation of (Na+,K+)-ATPase, and interactions between noradrenergic regulation of (Na+,K+)-ATPase and other mechanisms of Na+ Ca++ transport. 2) Experiments on specificity of transmitter regulation of (Na+,K+)-ATPase will examine specificity with respect to a) transmitter, receptor subtype, and tissue, b) molecular form of enzyme, using polyacrylamide gel electrophoresis to separate the two forms of enzyme, and c) localization of enzyme regulated by norepinephrine, using radioautography. The latter experiments will provide pilot data for development of studies using positron emission tomography. 3) Experiments on the mechanism of the noradrenergic effects will examine (Na+,K+)-ATPase-mediated transport in vitro. Initial experiments will compare effects in synaptosomes, dissociated brain cells, and brain slices. Further experiments will examine transmitter specificity, effects of prior exposure to norepinephrine, hormone status, or treatment with psychoactive drugs in vivo, effects of electrical stimulation in vitro, and roles of cation fluxes and of cyclic nucleotides. 4) Experiments in man will use stimulation of cation shifts by endogenous catecholamines to develop a means for examining noradrenergic regulation of (Na+,K+)-ATPase in intact man. These studies will provide the basis for studies of noradrenergic regulation of (Na+,K+)-ATPase in normal man and in conditions related to functions of the norepinephrine-(Na+,K+)-ATPase system, including affective disorders, eating disorders, and disorders of neural arousal.

本提案中的研究将审查 (Na+,K+)-ATP酶在体内通过去甲肾上腺素和特定的内源性 该酶的抑制剂。 (Na+,K+)-ATP酶是 能量依赖的 Na+ 和 K+ 运输，在 调节细胞内阳离子浓度，从而调节细胞膜 潜力、细胞兴奋性和能量利用。 实验在 该提案分为四个部分。 1) 检验调节的实验 (Na+,K+)-ATP酶以及去甲肾上腺素和甲状腺之间的相互作用或 肾上腺皮质激素对 (Na+,K+)-ATP 酶的调节及其相互作用 (Na+,K+)-ATP酶的去甲肾上腺素能调节与其他机制之间 Na+ Ca++ 运输。 2）发射机特异性实验 (Na+,K+)-ATPase 的调节将检查以下方面的特异性： 递质、受体亚型和组织，b) 酶的分子形式， 使用聚丙烯酰胺凝胶电泳分离两种形式 酶，以及 c) 受去甲肾上腺素调节的酶的定位，使用 放射自显影。 后面的实验将提供试点数据 使用正电子发射断层扫描的研究进展。 3）实验 去甲肾上腺素能作用的机制将检查 (Na+,K+)-ATP酶介导的体外转运。 初步实验将 比较突触体、分离脑细胞和大脑的效果 切片。 进一步的实验将检查递质的特异性、影响 之前接触过去甲肾上腺素、激素状态或接受过治疗 体内精神活性药物、体外电刺激的影响，以及 阳离子通量和环核苷酸的作用。 4）人体实验 将利用内源性儿茶酚胺刺激阳离子移动来 开发一种检查 (Na+,K+)-ATPase 去甲肾上腺素能调节的方法 在完好无损的人身上。 这些研究将为以下研究提供基础 正常人和条件下 (Na+,K+)-ATP 酶的去甲肾上腺素能调节 与去甲肾上腺素-(Na+,K+)-ATP酶系统的功能相关， 包括情感障碍、饮食障碍和神经障碍 唤醒。