Synaptic Mechanisms Regulating Sympathetic Drive

调节交感神经驱动的突触机制

基本信息

批准号：
7056798
负责人：
Hui-Lin Pan
金额：
$ 32.21万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7056798
关键词：
Angiotensin II Arachidonate 12-Lipoxygenase Area Arts Autonomic nervous system Biological Models Brain Brain Stem Cells Chemosensitization Condition Congestive Heart Failure Coupled Cyclic GMP Cyclic GMP-Dependent Protein Kinases Data Disease Disinhibition Fire - disasters GTP-Binding Proteins Hand Hypertension Hypothalamic structure Myocardial Infarction Myocardial Ischemia Nerve Neuraxis Neurons Nitric Oxide Oxides Pan Genus Pharmacology Phospholipase A2 Phosphoric Monoester Hydrolases Physiological Physiology Presynaptic Terminals Protein Kinase Protein phosphatase Rattus Regulation Research Personnel Role Signal Transduction Site Slice Spinal Spinal Cord Sympathetic Nervous System Synapses Techniques Testing Voltage-Gated Potassium Channel attenuation base cGMP-dependent protein kinase Ibeta gamma-Aminobutyric Acid immunocytochemistry in vivo paraventricular nucleus patch clamp presynaptic programs voltage

项目摘要

DESCRIPTION (provided by applicant): The sympathetic drive emanating from the brain is increased in many pathophysiological conditions including hypertension and congestive heart failure. The paraventricular nucleus (PVN) of the hypothalamus is an important site for the control of sympathetic outflow through its projections to the sympathetically related sites in the brainstem and spinal cord. It has been shown that angiotensin II (Ang II) increases the excitability of PVN presympathetic neurons by attenuation of the synaptic GABA release. On the other hand, nitric oxide (NO) inhibits PVN presympathetic neurons through potentiation of the GABAergic input. However, the important signal transduction mechanisms responsible for the presynaptic actions of Ang II and NO remain poorly understood. In this proposal, PVN neurons that project to the rostral ventrolateral medulla and spinal intermediolateral cell column in rats will be used as a model system to test the following specific hypotheses: 1) Ang II reduces the GABAergic synaptic input to PVN presympathetic neurons through voltage-gated K+ channels activated by 12-lipoxygenase products and phospholipase A2 coupled to inhibitory G proteins; 2) Nitric oxide potentiates synaptic GABA release onto PVN presympathetic neurons through inhibition of voltage-gated K+ channels, due to activation of protein phosphatases by protein kinase G; and 3) Kv1/Kv4 subunits that form voltage-gated K+ channels are located on GABAergic presynaptic terminals in the PVN. These hypotheses will be tested using a combination of in vivo retrograde tracing, whole-cell patch-clamp recording in rat brain slices, and immunocytochemistry techniques. These studies will provide important new information about the fundamental cellular and signaling mechanisms for the opposing presynaptic actions of Ang II and NO in the central nervous system. This information also will be important for our understanding of the synaptic mechanisms responsible for central regulation of the sympathetic nervous system in physiological and pathophysiological states such as hypertension, myocardial infarction, and congestive heart failure.

描述（由申请人提供）：在许多病理生理状况（包括高血压和充血性心力衰竭）中，从大脑发出的交感神经驱动会增加。下丘脑的室室核（PVN）是通过其投影到脑干和脊髓中的交感神经相关部位来控制交感神经流出的重要部位。已经表明，血管紧张素II（ANG II）通过衰减突触GABA释放增加了PVN头前神经元的兴奋性。另一方面，一氧化氮（NO）通过增强GABA能输入的增强抑制PVN的PVN PRVN神经元。但是，负责ANG II的突触前作用的重要信号转导机制，没有知识不足。在该提案中，将大鼠的鼻腹外侧髓质和脊柱间中外侧细胞柱投射的PVN神经元将用作测试以下特定假设的模型系统：1）ANG II减少GABA能突触输入到PVN预感，通过pvn Prttage-Entertagetic神经元通过电压 - 交感神经元减少由12-脂氧合酶产物和磷脂酶A2激活的门控k+通道与抑制性G蛋白相连； 2）一氧化氮增强突触GABA通过抑制电压门控的K+通道释放到PVN的PVN PEVN PRENTACTY神经元上，这是由于蛋白激酶G激活了蛋白质磷酸酶； 3）形成电压门控的K+通道的KV1/KV4亚基位于PVN中的GABA能突触前末端。这些假设将通过体内逆行跟踪，大鼠脑切片中的全细胞贴片钳记录和免疫细胞化学技术的组合进行测试。这些研究将提供有关中枢神经系统中ANG II的相对突触前作用的基本细胞和信号传导机制的重要新信息。这些信息对于我们理解负责在生理和病理生理状态（例如高血压，心肌梗死和充血性心力衰竭）中的共同神经系统中心调节的突触机制也很重要。