Receptor Targeting and Plasticity in NTS

NTS 中的受体靶向和可塑性

• 批准号: 7088874
• 负责人: VIRGINIA M PICKEL
• 金额: $ 32.99万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7088874
• 关键词: AMPA receptors; NAD(P)H dehydrogenase; angiotensin receptor; baroreceptors; baroreflex; calcium channel; catecholamines; cell membrane; electron microscopy; free radical oxygen; glutamates; hypertension; immunocytochemistry; laboratory rat; neural plasticity; solitary tract nucleus; voltage /patch clamp; voltage gated channel

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)是化学反射引起的血压升高和高血压引起的压力感受器反射重置的最主要的脑区，两者都可以通过激活局部血管紧张素受体(AT1)来调节。项目2将验证中心假设，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氧化酶与血管紧张素II(Ang11)的急性和长期影响有关。这将通过(1)相关受体和NAD(P)H氧化酶亚基的高分辨电子显微镜免疫细胞化学双重标记和(2)超微结构分析和膜片钳记录在大鼠NTS的Dia顺行运输中识别的压力感觉神经元来实现。有5个具体目标。AIMS 1和2将验证AT1和α2肾上腺素能受体共同定位于NTS突触前轴突或其树突靶点的假设，它们的分布与它们的激动剂对化学或压力感觉神经元的相反作用是一致的。目的3验证血管紧张素Ⅱ在NTS压力感觉神经元的生理作用是通过开放电压依赖性的钙通道来实现的，该通道也受NAD(P)H氧化酶产生的活性氧物种(ROS)的影响，其亚单位存在于许多含有AT1受体的细胞中。电压门控钙通道的开放对于NMDA和某些类型的AMPA受体的激活是必不可少的，它们分别是化学感觉和压力感觉传递的主要媒介。这些受体与NAD(P)H氧化酶一样，由多个亚基组成，对质膜和质膜具有活性依赖的动员作用。谷氨酸(AIM 4)或NAD(P)H氧化酶(AIM 5)亚基免疫金标记亚细胞分布的变化将被用来研究这种可塑性在慢性间歇性低氧引起的睡眠呼吸暂停大鼠模型或Ang11诱导的高血压大鼠血压升高中的潜在作用。综上所述，这些结果将有助于理解大脑机制的发展和维持 高血压。