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Function of the Sigma-1 Receptor in Motoneurons

运动神经元中 Sigma-1 受体的功能

基本信息

批准号：
8411144
负责人：
Arnold Eino Ruoho
金额：
$ 18.15万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-15 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8411144
关键词：
Action Potentials Age Agonist Amyotrophic Lateral Sclerosis Animals Behavior Behavioral C-terminal Cell membrane Data Development Disease Electrophysiology (science)Elements Endoplasmic Reticulum Frequencies Functional disorder Gastrocnemius Muscle Goals Knock-out Knockout Mice Lead Life Ligands Light Longevity Mediating Modeling Monitor Motor Motor Activity Motor Neurons Mus Muscle Muscle Contraction Neuraxis Output Pathology Pharmaceutical Preparations Play Positioning Attribute Postsynaptic Membrane Potassium Channel Proteins Role Site Speed Spinal Spinal Cord Steroids Stress Swimming Synapses Testing Up-Regulation Weight Work base cholinergic density design expectation experience mouse model neuronal excitability novel novel therapeutics postsynaptic presynaptic prevent response reticulum cell sigma-1 receptor treatment strategy

项目摘要

The Sigma-1 receptor (S1R) is a 26 kDa protein found in portions of the endoplasmic reticulum (ER) of cells. In the central nervous system the highest levels of the S1R (CNS) are found in the postsynaptic portions of cholinergic postsynaptic densities (C-terminals) of spinal cord motoneurons. The primary objective of this proposal is to evaluate the role of SIR in regulating the excitability of motoneurons. We hypothesize that the S1R plays a direct role in regulating motoneuron excitability by activation of SK and/or Kv2.1 potassium channels in C-terminals, the effect of which is to increase the amplitude of the afterhyperpolarization potential (AHP) and thereby to reduce the frequency and duration of action potential firing. We hypothesize that activation of S1R can increase longevity of ALS mice by acting as a neuromodulatory "brake" on motoneuron hyperexcitability and thereby to decrease intracellular stress. We will accomplish the goals of this proposal through the following specific aims: Specific Aim 1: To determine whether S1R modulates motoneuron excitability (Electrophysiology) and influences the amplitude of electrical activity of the gastrocnemius muscle. (Motor activity). Specific Aim 2: To establish that activation of S1R can retard the progression of motoneuron degeneration in a mouse model of ALS (Pathology) by a) assessing survival of a new mouse model SOD1 ALS/S1R KO compared to the SOD1 ALS/S1R WT mice and b) assessing survival of the SOD1 ALS/S1R KO and the SOD1 ALS/S1R WT mice in the presence and absence of agonists of the S1R. Targeting S1R can potentially establish a new therapeutic treatment for ALS.

Sigma-1受体（S1 R）是一种26 kDa的蛋白质，存在于小鼠的内质网（ER）部分，细胞在中枢神经系统中，最高水平的S1 R（CNS）存在于突触后脊髓运动神经元的胆碱能突触后密度（C-末端）的部分。主本研究的目的是评价SIR在调节运动神经元兴奋性中的作用。我们假设S1 R通过激活SK和/或 Kv2.1钾通道的C-末端，其作用是增加的幅度，后超极化电位（AHP），从而减少动作电位的频率和持续时间击发我们假设S1 R的激活可以通过作为一种免疫调节剂来延长ALS小鼠的寿命。因此，本发明提供了对运动神经元过度兴奋性的神经调节“制动”，从而降低细胞内应激。我们将通过以下具体目标实现本提案的目标：具体目标1：确定 S1 R是否调节运动神经元兴奋性（电生理学）并影响腓肠肌的电活动。（运动）。具体目标2：建立激活 S1 R的表达可以通过以下方式延缓ALS小鼠模型中运动神经元变性的进展（病理学）：评估新小鼠模型SOD 1 ALS/S1 R KO与SOD 1 ALS/S1 R WT小鼠相比的存活率和B）评估在存在和/或不存在SOD 1 ALS/S1 R KO和SOD 1 ALS/S1 R WT小鼠的情况下SOD 1 ALS/S1 R KO和SOD 1 ALS/S1 R WT小鼠的存活率，不存在S1 R激动剂。靶向S1 R可以潜在地建立一种新的治疗方法，人症

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Noncompetitive inhibition of indolethylamine-N-methyltransferase by N,N-dimethyltryptamine and N,N-dimethylaminopropyltryptamine.

DOI：
10.1021/bi500175p
发表时间：
2014-05-13
期刊：
Biochemistry
影响因子：
2.9
作者：
Chu UB;Vorperian SK;Satyshur K;Eickstaedt K;Cozzi NV;Mavlyutov T;Hajipour AR;Ruoho AE
通讯作者：
Ruoho AE

N-terminus regulation of VMAT2 mediates methamphetamine-stimulated efflux.

VMAT2 的 N 端调节介导甲基苯丙胺刺激的外流。