Synaptic Mechanisms of General Anesthetic Action

全身麻醉作用的突触机制

基本信息

批准号：
10624971
负责人：
HUGH C HEMMINGS
金额：
$ 52.45万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624971
关键词：
Affect Amnesia Anesthetics Behavioral Binding Sites Brain region Calcium Calcium Channel Cardiovascular system Cells Circular Dichroism Clinical Collaborations Coupled Data Dendritic Spines Development Dose Electrophysiology (science)Endoplasmic Reticulum Exocytosis Future General Anesthesia General anesthetic drugs Glutamates Goals Hippocampus Homologous Gene Human Resources Image Immobilization Impaired cognition Interneurons Ion Channel Isoflurane Knowledge London Malignant hyperpyrexia due to anesthesia Medicine Mental Depression Methods Modeling Modern Medicine Molecular Molecular Probes Mutation NMR Spectroscopy Nerve Neurons Neurosciences Neurotransmitters Outcome Pain Patients Pharmaceutical Preparations Phenotype Predisposition Property Publishing Regulation Research Research Proposals Role RyR1 Ryanodine Receptor Calcium Release Channel Site Sodium Channel Structure Synapses Synaptic Transmission Synaptic Vesicles Techniques Testing Therapeutic Unconscious State Universities Volatilization X-Ray Crystallography base biophysical techniques college experience gamma-Aminobutyric Acid high risk imaging approach improved in vivo innovation interdisciplinary approach molecular subtypes multidisciplinary neurophysiology neurotoxicity neurotransmitter release novel postsynaptic presynaptic prototype receptor respiratory response side effect structural biology synaptic inhibition uptake voltage

项目摘要

Abstract Despite widespread clinical use, knowledge of the mechanisms of general anesthetics is insufficient to explain how they produce amnesia, unconsciousness or immobilization (with increasing doses), the cardinal features of general anesthesia. The long-term goal of this project is to define the synaptic mechanisms that underlie the actions of general anesthetics on the CNS. Anesthetics have potent and specific effects on synaptic transmission, including both presynaptic actions on the release of neurotransmitters and postsynaptic actions on receptors and dendritic spines. The principal objective of this research proposal is to understand synapse- specific presynaptic effects of volatile anesthetics which are poorly understood. Our central hypothesis is that general anesthetics have synapse-specific mechanisms resulting in selective effects on presynaptic ion channels and exocytosis. The rationale underlying this proposal is that understanding presynaptic anesthetic actions relevant to their therapeutic (unconsciousness, amnesia, immobility) and toxic (neurotoxicity, cognitive dysfunction, respiratory and cardiovascular depression) effects of anesthetics is essential for developing new anesthetics with improved side-effect profiles and for optimizing current anesthetic techniques in increasingly high-risk patients. Our proposal that volatile anesthetics have distinct effects on the release of various neurotransmitters due to differential presynaptic expression of anesthetic-sensitive ion channels coupled to transmitter release, in particular voltage-gated sodium and calcium channels, is innovative in approach and employs recently developed techniques in neuroscience and structural biology. The central hypothesis will be tested using an integrative and collaborative multidisciplinary approach by the following three specific aims employing in vivo, cellular and molecular methods: 1) Identify nerve terminal-specific presynaptic mechanisms that influence the sensitivity of synaptic vesicle exocytosis to volatile anesthetics to test the hypothesis that volatile anesthetics differentially inhibit synaptic vesicle exocytosis by nerve terminal-specific mechanisms resulting from heterogeneous presynaptic ion channel expression; 2) Determine the effects of volatile anesthetics on neuronal intracellular Ca2+ regulation and its impact on synaptic vesicle exocytosis to test the hypothesis that volatile anesthetic effects on intracellular Ca2+ dynamics influence synaptic vesicle exocytosis; and 3) Identify volatile anesthetic binding sites on voltage-gated sodium channels using the bacterial homologue NavMs to test the hypothesis that volatile anesthetic inhibition involves direct interactions. The research is significant in applying multidisciplinary and complementary electrophysiological, biophysical, and imaging approaches involving a team of expert collaborators. The expected outcome is a molecular understanding of synaptic anesthetic mechanisms underlying desirable and potentially toxic anesthetic effects on excitatory and inhibitory synaptic transmission. Our results will have positive impact on the rational use and future development of general anesthetics, an increasingly important class of essential medicines.

抽象的尽管广泛使用临床使用，但对一般麻醉的机制的了解不足以解释它们如何产生失忆，无意识或固定（随剂量增加），主要特征全身麻醉。该项目的长期目标是定义基于的突触机制通用麻醉剂在中枢神经系统上的作用。麻醉药对突触具有有效的特定作用传播，包括对神经递质释放和突触后作用的突触前作用在受体和树突状的刺上。该研究建议的主要目的是了解突触 - 挥发性麻醉剂的特定突触前作用知之甚少。我们的中心假设是一般麻醉具有突触特异性机制，从而对突触前离子产生选择性影响通道和胞吐作用。该提议的基本原理是理解突触前麻醉剂与他们的治疗性（无意识，健忘症，不动）和有毒（神经毒性，认知能力，认知）相关的行动功能障碍，呼吸道和心血管抑郁）麻醉的作用对于开发新的作用至关重要麻醉药具有改善的副作用曲线，并在越来越多地优化电流麻醉技术高危患者。我们提出的关于挥发性麻醉药对各种释放有明显影响的建议神经递质是由于麻醉敏感离子通道的突触前表达差异引起的发射机释放，尤其是电压门控钠和钙通道，在方法上是创新的，采用最近开发的神经科学和结构生物学技术。中心假设将是通过以下三个特定目标使用综合和协作的多学科方法测试采用体内，细胞和分子方法：1）识别神经终末特异性的突触前机理这会影响突触囊泡胞吐作用对挥发性麻醉的敏感性，以检验以下假设。挥发性麻醉剂差异地抑制神经终末特异性机制的突触囊泡胞吐作用由异质突触前离子通道表达产生； 2）确定挥发性的影响神经元内CA2+调节的麻醉剂及其对突触囊泡胞吐作用的影响以测试假设挥发性麻醉对细胞内Ca2+动力学影响会影响突触囊泡胞吐作用； 3）使用细菌识别电压门控钠通道上的挥发性麻醉结合位点同源物NAVMS测试挥发性麻醉抑制涉及直接相互作用的假设。这研究对于应用多学科和互补的电生理，生物物理和涉及专家合作者团队的成像方法。预期的结果是分子了解突触麻醉机制所需的理想和潜在有毒麻醉作用的理解在兴奋性和抑制性突触传播上。我们的结果将对合理使用产生积极影响以及一般麻醉药的未来发展，这是日益重要的基本药物类别。

项目成果

期刊论文数量（63）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Volatile anesthetics inhibit sodium channels without altering bulk lipid bilayer properties.

DOI：
10.1085/jgp.201411172
发表时间：
2014-12
期刊：
The Journal of general physiology
影响因子：
0
作者：
Herold KF;Sanford RL;Lee W;Schultz MF;Ingólfsson HI;Andersen OS;Hemmings HC Jr
通讯作者：
Hemmings HC Jr

Anesthetic properties of 4-iodopropofol: implications for mechanisms of anesthesia.

4-碘丙泊酚的麻醉特性：对麻醉机制的影响。

DOI：
10.1097/00000542-200106000-00020
发表时间：
2001
期刊：
Anesthesiology
影响因子：
8.8
作者：
Lingamaneni,R;Krasowski,MD;Jenkins,A;Truong,T;Giunta,AL;Blackbeer,J;MacIver,MB;Harrison,NL;HemmingsJr,HC
通讯作者：
HemmingsJr,HC

Regional differences in nerve terminal Na+ channel subtype expression and Na+ channel-dependent glutamate and GABA release in rat CNS.