Synaptic Mechanisms Regulating Sympathetic Drive

调节交感神经驱动的突触机制

• 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
• 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

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）：在包括高血压和充血性心力衰竭在内的许多病理生理条件下，来自大脑的交感驱动增加。下丘脑室旁核（PVN）通过投射到脑干和脊髓的交感神经相关部位，是控制交感神经流出的重要部位。研究表明，血管紧张素II （Ang II）通过抑制突触GABA的释放而增加PVN前交感神经元的兴奋性。另一方面，一氧化氮（NO）通过增强gaba能输入抑制PVN前交感神经元。然而，对Ang II和NO突触前作用的重要信号转导机制仍知之甚少。本研究以大鼠PVN神经元投射至延髓吻侧腹外侧和脊柱中外侧细胞柱为模型系统，验证以下具体假设：1)Ang II通过12-脂氧合酶产物和磷脂酶A2偶联抑制G蛋白激活的电压门控K+通道，减少gaba能突触输入到PVN前交感神经元；2)由于蛋白激酶G激活蛋白磷酸酶，一氧化氮通过抑制电压门控K+通道，增强突触向PVN前交感神经元释放GABA；3)形成电压门控K+通道的Kv1/Kv4亚基位于PVN的gaba能突触前末端。这些假设将通过体内逆行追踪、大鼠脑切片全细胞膜片钳记录和免疫细胞化学技术的组合来验证。这些研究将为中枢神经系统中Ang II和NO突触前作用的基本细胞和信号机制提供重要的新信息。这一信息对于我们理解交感神经系统在生理和病理生理状态（如高血压、心肌梗死和充血性心力衰竭）中中枢调节的突触机制也很重要。