Function of the Sigma-1 Receptor in Motoneurons

描述（由申请方提供）：Sigma-1受体（S1 R）是一种在细胞内质网（ER）部分中发现的26 kDa蛋白质。在中枢神经系统中，在脊髓运动神经元的胆碱能突触后密度（C-末端）的突触后部分中发现最高水平的S1 R（CNS）。该建议的主要目的是评估S1 R在调节运动神经元兴奋性中的作用。我们推测S1 R通过激活运动神经元的兴奋性直接调节运动神经元的兴奋性。 C-末端的SK和/或Kv2.1钾通道，其作用是增加后超极化电位（AHP）的幅度，从而减少动作电位放电的频率和持续时间。我们假设S1 R的激活可以通过对运动神经元的过度兴奋起到神经调节的“制动”作用，从而降低细胞内的应激，从而延长ALS小鼠的寿命。我们将通过以下具体目标来实现本提案的目标：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）并影响腓肠肌电活动的幅度。（运动）。具体目标二：通过a）评估与SOD 1 ALS/S1 R WT小鼠相比，新小鼠模型SOD 1 ALS/S1 R KO的存活率，和B）评估存在和不存在S1 R激动剂时SOD 1 ALS/S1 R KO和SOD 1 ALS/S1 R WT小鼠的存活率，确定S1 R激活可延缓ALS（病理学）小鼠模型中运动神经元变性的进展。靶向S1 R可能为ALS建立一种新的治疗方法。 公共卫生相关性：该提案中的假设是Sigma-1受体对神经元兴奋性起着“制动”作用。随着神经元兴奋性的降低，运动神经元经历较少的细胞损伤，从而在肌萎缩性侧索硬化症（Lou Gehrig病）的发展期间保持功能更长的时间。我们希望用特定的药物激活Sigma-1受体将进一步减少细胞损伤，并为Lou Gehrig病带来新的治疗策略。

DESCRIPTION (provided by applicant): 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 S1R 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. PUBLIC HEALTH RELEVANCE: The hypothesis in this proposal is that the Sigma-1 receptor acts as a "brake" on neuronal excitability. With a reduction in neuronal excitability motoneurons experience less cellular damage and thereby remain functional for a longer period during the development of Amyotrophic Lateral Sclerosis (Lou Gehrig's disease). We expect that activating the Sigma-1 receptor with specific drugs will further reduce cellular damage and lead to new treatment strategies for Lou Gehrig's disease.