Function of the Sigma-1 Receptor in Motoneurons

Sigma-1受体(S1R)是一种大小为26 kDa的蛋白质，存在于大鼠的部分内质网中。 细胞。在中枢神经系统中，S1R(CNS)的最高水平出现在突触后 脊髓运动神经元的部分胆碱能突触后密度(C-终末)。初级阶段 本研究的目的是评价SIR在运动神经元兴奋性调节中的作用。我们 假设S1R通过激活SK和/或在调节运动神经元兴奋性中起直接作用 Kv2.1钾通道在C-末端，其作用是增加 后超极化电位(AHP)，从而减少动作电位的频率和持续时间 开火。我们假设S1R的激活可以通过作为一种 神经调节“刹车”运动神经元的过度兴奋性，从而减少细胞内的应激。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 S1R是否调制运动神经元兴奋性(电生理学)并影响其波幅 腓肠肌的电活动。(运动活动)。具体目标2：确定激活 S1R可延缓ALS(病理)小鼠模型运动神经元变性的进程。 一种新的小鼠模型SOD1ALS/S1R KO与SOD1ALS/S1R WT小鼠的比较 以及b)评估SOD1ALS/S1R KO和SOD1ALS/S1R WT小鼠在存在和 缺乏S1R激动剂。靶向S1R可能会建立一种新的治疗方法 肌萎缩侧索硬化。

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.