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.

孤立道（NTS）的核是大脑区域与化学反射诱导的血压升高和压力受体反射的高血压诱发的重置，这两者都可以通过激活局部血管紧张素-1（AT1）受体来调节。项目2将检验一个中心假设：NT中的AT1受体具有亚细胞分布，支持直接参与Cherno和/或/或/或安排体感反射，以及与儿茶酚胺和NAD（P）H氧化酶的相互作用，这是一种与Angiotens II（Anglly）急性和长期作用有关的酶。这将通过（1）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双重化学双重标记，以及（2）通过RAP NTS中DIA鉴定出的干压神经元的超微结构分析和斑块钳记录。有5个具体目标。目标1和2将检验以下假设：AT1和α2-肾上腺素能受体在突触前轴突中共定位在NTS中，在NTS中的树突状靶标的分布与激动剂对化学或大型神经元的相反作用一致。 AIM 3将检验以下假设：NTS大压神经元中ANG II的生理作用是通过开放依赖电压依赖性Ca 2+通道介导的，也受到由NAD（P）H氧化酶产生的活性氧（ROS）影响的，其亚基存在于许多包含AT1受体的细胞中。电压门控Ca 2+通道的打开对于分别是化学感应和总压敏传播的主要介体的NMDA和某些类型的AMPA受体至关重要。这些受体，例如NAD（P）H氧化酶，由多个亚基组成，表现出活性依赖于血浆和细胞质膜的动员。谷氨酸免疫金标记的亚细胞分布的变化（AIM 4）或NAD（P）H氧化酶（AIM 5）亚基将用于研究该可塑性在慢性间歇性低氧在睡眠呼吸暂停的大鼠模型中产生的血压高程中的潜在作用，或者共同的结果将有助于理解开发和维护的基础的大脑机制 高血压。