VOLATILE ANESTHETICS AND NEURONAL CALCIUM

挥发性麻醉剂和神经钙

基本信息

批准号：
8073858
负责人：
THOMAS Joseph John BLANCK
金额：
$ 7.12万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8073858
关键词：
Absence of pain sensation Action Potentials Adult Amnesia Anesthesia procedures Anesthetics Anterior Horn Cells Axon Biological Models Brain region Calcium Cell membrane Cells Chemicals Cytosol Data Dendrites Dependence Doctor of Philosophy Drug effect disorder Endoplasmic Reticulum Environment Enzymes Excitatory Postsynaptic Potentials Fluorescence GTP-Binding Proteins Glutamate Receptor Glutamates Halothane Horns Human Image Individual Isoflurane Ligands Maintenance Measures Mediating Membrane Potentials Mental Depression Methodology Mitochondria Molecular Motor Neurons Mus Muscle Muscle relaxation phase Nerve Neuroblastoma Neurons Pathway interactions Phosphorylation Physiological Play Presynaptic Terminals Rattus Receptor Activation Regulation Reporting Rest Role Signal Transduction Site Spinal Spinal Cord Spinal Ganglia Stimulus Surface Synaptosomes Testing Trees Unconscious State Ventral Horn of the Spinal Cord extracellular insight neuronal cell body neuronal excitability neurotransmission neurotransmitter release presynaptic prospective protein activation receptor response synaptic inhibition transmission process voltage

项目摘要

DESCRIPTION (provided by applicant): Immobility mediated by volatile anesthetics (VAs) appears to result largely from depression of excitatory neurotransmission at the spinal cord level. Neurons transform electrical and chemical stimuli into meaningful physiological signals by the regulation of intracellular Ca2+ concentration and compartmentalization. Chemicals that act at particular Ca2+ regulatory sites have been shown to alter the MAC of VAs. At the cellular level, VAs have been shown to inhibit voltage-dependent Ca2+ channels and Ca2+ transients in neuronal cells. We hypothesize that Volatile anesthetics produce immobility by inhibiting spinal cord neurons through the modulation of Ca2+ channels and signaling. We will test this hypothesis by comparing the effects of tree VAs, isoflurane, halothane, and F3, with that of two structurally related molecules that fail to produce immobility (non-immobilizers (NIMs)), F6 and F8. Effects on voltage-dependent (L- and N-type) and ligand (glutamate)-activated Ca2+ channels, glutamate-mediated neuronal excitability, and glutamate release from synaptosomes will be explored. Initial studies will involve human SH-SY5Y neuroblastoma cells as a model system to identify prospective targets of drug action. We will also study dorsal root ganglion neurons (DRG), and spinal ventral horn (VH)- motor neurons in primary culture as well as synaptosomes, all isolated from the adult rat spinal cord. The specific aims will determine whether VAs and NIMs (1) differ in their block of plasma membrane L- and N-type voltage dependent Ca2+ channels; (2a) differ in their block of capacitative- glutamate activated cationic Ca2+ channels; (2b) change the sensitivity of glutamate for evoking cytoplasmic Ca2+ transients, and action on glutamate-activated ionotropic and/or metabotropic receptors; and (2c) differ in their effect on the presynaptic release of glutamate from spinal cord synaptosomes and its dependence on Ca2+. Whole cell and patch voltage- and current-clamp, and fluorescence methodologies including imaging for measuring intracellular Ca2+, plasma membrane potential, and glutamate release will be employed. The results of these studies will yield important molecular insights into Ca2+ signaling in neurons and clarify the relevance of VA effects on Ca2+ signaling to the immobility aspect of VA-mediated anesthesia.

描述（由申请人提供）：由挥发性麻醉剂（VA）介导的不动似乎主要是由于脊髓水平的兴奋性神经传递抑制所致。神经元通过调节细胞内 Ca2+ 浓度和区室化，将电和化学刺激转化为有意义的生理信号。作用于特定 Ca2+ 调节位点的化学物质已被证明可以改变 VA 的 MAC。在细胞水平上，VA 已被证明可以抑制神经元细胞中电压依赖性 Ca2+ 通道和 Ca2+ 瞬变。我们假设挥发性麻醉剂通过调节 Ca2+ 通道和信号传导来抑制脊髓神经元，从而产生不动性。我们将通过比较树 VA、异氟烷、氟烷和 F3 的效果与无法产生固定性的两种结构相关分子（非固定剂 (NIM)）F6 和 F8 的效果来检验这一假设。将探讨对电压依赖性（L 型和 N 型）和配体（谷氨酸）激活的 Ca2+ 通道、谷氨酸介导的神经元兴奋性以及突触体释放谷氨酸的影响。初步研究将使用人类 SH-SY5Y 神经母细胞瘤细胞作为模型系统来识别药物作用的潜在靶点。我们还将研究原代培养物中的背根神经节神经元 (DRG) 和脊髓腹角 (VH) 运动神经元以及突触体，所有这些都从成年大鼠脊髓中分离出来。具体目标将确定 VA 和 NIM 是否在阻断质膜 L 型和 N 型电压依赖性 Ca2+ 通道方面存在差异； (2a) 其对电容性谷氨酸激活的阳离子 Ca2+ 通道的阻断不同； (2b)改变谷氨酸引起细胞质Ca2+瞬变的敏感性，以及对谷氨酸激活的离子型和/或代谢型受体的作用； (2c) 和 (2c) 对脊髓突触体突触前释放谷氨酸的影响及其对 Ca2+ 的依赖性不同。将采用全细胞和贴片电压钳和电流钳以及荧光方法，包括用于测量细胞内 Ca2+、质膜电位和谷氨酸释放的成像。这些研究的结果将为神经元中 Ca2+ 信号传导提供重要的分子见解，并阐明 VA 对 Ca2+ 信号传导的影响与 VA 介导的麻醉的不动方面的相关性。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anemone toxin II unmasks two conductance states in neuronal sodium channels.

海葵毒素 II 揭示神经元钠通道中的两种电导状态。

DOI：
10.1016/0006-8993(96)00566-5
发表时间：
1996
期刊：
Brain research
影响因子：
2.9
作者：
Castillo,C;Piernavieja,C;Recio-Pinto,E
通讯作者：
Recio-Pinto,E

Transient effects of anesthetics on dendritic spines and filopodia in the living mouse cortex.

DOI：
10.1097/aln.0b013e318229a660
发表时间：
2011-10
期刊：
Anesthesiology
影响因子：
8.8
作者：
Yang G;Chang PC;Bekker A;Blanck TJ;Gan WB
通讯作者：
Gan WB

Isoflurane, but Not the Nonimmobilizers F6 and F8, Inhibits Rat Spinal Cord Motor Neuron CaV1 Calcium Currents.

DOI：
10.1213/ane.0000000000001111
发表时间：
2016-03
期刊：
Anesthesia and analgesia
影响因子：
5.7
作者：
Recio-Pinto E;Montoya-Gacharna JV;Xu F;Blanck TJJ
通讯作者：
Blanck TJJ

Despite differences in cytosolic calcium regulation, lidocaine toxicity is similar in adult and neonatal rat dorsal root ganglia in vitro.

DOI：
10.1097/aln.0b013e3182a2a561
发表时间：
2014-01
期刊：
Anesthesiology
影响因子：
8.8
作者：
Doan LV;Eydlin O;Piskoun B;Kline RP;Recio-Pinto E;Rosenberg AD;Blanck TJ;Xu F
通讯作者：
Xu F

G-protein activation decreases isoflurane inhibition of N-type Ba2+ currents.

G 蛋白激活可减少异氟烷对 N 型 Ba2 电流的抑制。