Function of the Sigma-1 Receptor in Motoneurons

描述(申请人提供)：Sigma-1受体(S1R)是一种26 kDa的蛋白质，存在于细胞的内质网(ER)的一部分。在中枢神经系统，S1R(CNS)在脊髓运动神经元的胆碱能突触后密度(C-末梢)的突触后部分表达最高。本研究的主要目的是评价S1R在运动神经元兴奋性调节中的作用。我们假设S1R通过激活S1R在调节运动神经元兴奋性中起直接作用。 其作用是增加后超极化电位(AHP)的幅度，从而缩短动作电位的放电频率和持续时间。我们推测S1R的激活可以通过对运动神经元的过度兴奋性起到神经调节“刹车”的作用来延长ALS小鼠的寿命，从而减少细胞内的应激。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S1R是否调节运动神经元的兴奋性(电生理学)并影响腓肠肌的电活动幅度。(运动活动)。具体目的2：通过a)评估新小鼠模型SOD1ALS/S1R KO与SOD1ALS/S1R WT小鼠的存活率，以及b)评估SOD1ALS/S1R KO和SOD1ALS/S1R WT小鼠在存在和不存在S1R激动剂的情况下的存活率，建立S1R的激活可以延缓ALS(病理学)小鼠模型中运动神经元变性的进展。靶向S1R可能为ALS建立一种新的治疗方法。 与公共健康相关：这项建议中的假设是，Sigma-1受体对神经元的兴奋性起到“刹车”的作用。随着神经元兴奋性的降低，运动神经元遭受的细胞损伤较少，因此在肌萎缩侧索硬化症(Lou Gehrig病)的发展过程中保持较长时间的功能。我们预计，用特定的药物激活Sigma-1受体将进一步减少细胞损伤，并导致Lou Gehrig病的新治疗策略。

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.