Receptor Targeting and Plasticity in NTS

NTS 中的受体靶向和可塑性

• 批准号: 7439025
• 负责人: VIRGINIA M PICKEL
• 金额: $ 37.02万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7439025
• 关键词: AMPA Receptors; Acute; Adrenergic Receptor; Affect; Agonist; Angiotensin II; Angiotensins; Axon; Baroreflex; Blood Pressure; Brain; Brain region; Catecholamines; Cell membrane; Cells; Chronic; Development; Electrons; Elevation; Enzymes; Glutamates; Hypertension; Hypoxia; Label; Localized; Long-Term Effects; Maintenance; Mediating; Mediator of activation protein; Microscopic; Modeling; N-Methylaspartate; NAD(P)H oxidase; Neurons; Nucleus solitarius; Physiological; Plasma; Rattus; Reactive Oxygen Species; Reflex action; Resolution; Role; Sleep Apnea Syndromes; Testing; anterograde transport; patch clamp; presynaptic; receptor; transmission process; voltage

The nucleus of the solitary tract (NTS) is the brain region most implicated in chemoreflex-induced blood pressure elevation and hypertension-evoked resetting of baroreceptor reflexes, both of which can be modulated through activation of local angiotensin-1 (AT1) receptors. Project 2 will test the central hypothesis that AT1 receptors in the NTS have subcellular distributions supporting direct involvement in cherno- and/or barosensory reflexes and interactions with both catecholamines and NAD(P)H oxidase, an enzyme implicated in the acute and long-term effects of angiotensin II (Angll). This will be achieved by using (1) high resolution electron microscopic immunocytochemical dual labeling of the relevant receptors and NAD(P)H oxidase subunits, and (2) both ultrastructural analysis and patch-clamp recording in barosensory neurons identified by anterograde transport of DiA in rat NTS. There are 5 Specific Aims. Aims 1 and 2 will test the hypothesis that AT1 and alpha2-adrenergic receptors are co-localized within presynaptic axons or their dendritic targets in the NTS, where their distributions are consistent with opposing actions of their agonists on chemo- or barosensory neurons. Aim 3 will test the hypothesis that the physiological actions of Ang II in NTS barosensory neurons are mediated through opening of voltage-dependent Ca 2+ channels also affected by reactive oxygen species (ROS) generated by NAD(P)H oxidase, whose subunits are present in many of the cells that contain AT1 receptors. The opening of voltage-gated Ca 2+ channels is essential for activation of NMDA and certain types of AMPA receptors that are the major mediators of chemosensory and barosensory transmission, respectively. These receptors, like NAD(P)H oxidase, are composed of multiple subunits showing activity-dependent mobilization to plasma and cytoplasmic membranes. Changes in the subcellular distribution of immunogold labeling for glutamate (Aim 4) or NAD(P)H oxidase (Aim 5) subunits will be used to study the potential role of this plasticity in the blood pressure elevations produced either by chronic intermittent hypoxia in the rat model of sleep apnea, or Angll-induced hypertension. Together, the results will contribute to understanding the brain mechanisms underlying the development and maintenance of hypertension.

孤束核 (NTS) 是与化学反射引起的血压升高和高血压诱发的压力感受器反射重置最相关的大脑区域，这两种情况都可以通过局部血管紧张素 1 (AT1) 受体的激活进行调节。项目 2 将测试中心假设，即 NTS 中的 AT1 受体具有亚细胞分布，支持直接参与切尔诺和/或压力感觉反射以及与儿茶酚胺和 NAD(P)H 氧化酶的相互作用，NAD(P)H 氧化酶是一种与血管紧张素 II (AngII) 的急性和长期效应有关的酶。这将通过使用（1）相关受体和 NAD(P)H 氧化酶亚基的高分辨率电子显微镜免疫细胞化学双重标记，以及（2）通过大鼠 NTS 中 DiA 顺行转运鉴定的压力感觉神经元的超微结构分析和膜片钳记录来实现。有 5 个具体目标。目标 1 和 2 将检验以下假设：AT1 和 α2 肾上腺素受体共定位于突触前轴突或其 NTS 中的树突靶标内，其中它们的分布与其激动剂对化学或压力感觉神经元的相反作用一致。目标 3 将检验以下假设：NTS 压力感觉神经元中 Ang II 的生理作用是通过打开电压依赖性 Ca 2+ 通道介导的，该通道还受到 NAD(P)H 氧化酶产生的活性氧 (ROS) 的影响，NAD(P)H 氧化酶的亚基存在于许多含有 AT1 受体的细胞中。电压门控 Ca 2+ 通道的开放对于 NMDA 和某些类型的 AMPA 受体的激活至关重要，这些受体分别是化学感应和压力感应传递的主要介质。这些受体，如 NAD(P)H 氧化酶，由多个亚基组成，表现出活性依赖性动员到质膜和细胞质膜。谷氨酸（目标 4）或 NAD(P)H 氧化酶（目标 5）亚基的免疫金标记的亚细胞分布的变化将用于研究这种可塑性在睡眠呼吸暂停大鼠模型中慢性间歇性缺氧或 Angll 诱导的高血压引起的血压升高中的潜在作用。总之，这些结果将有助于理解大脑发育和维持的机制 高血压。