Mechanical Activation of NMDA Receptors

NMDA 受体的机械激活

• 批准号: 9329498
• 负责人: Gabriela K Popescu
• 金额: $ 23.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329498
• 关键词: Affect; Alzheimer' s Disease; Apoptosis; Astrocytes; Automobiles; Biological Process; Brain; Brain Concussion; Calcium; Cell physiology; Cells; Cellular Assay; Characteristics; Cues; Development; Diffuse Axonal Injury; Electrophysiology (science); Excitatory Synapse; Fluorometry; Functional disorder; Glutamate Receptor; Glutamates; Hippocampus (Brain); Huntington Disease; Inflammation; Injury; Ion Channel; Ion Channel Protein; Kinetics; Knowledge; Location; Longevity; Mechanics; Membrane; Molecular; Monitor; N-Methyl-D-Aspartate Receptors; Neuraxis; Neurologic Effect; Neurons; Neurotransmitters; Optical Methods; Parkinson Disease; Pathologic; Pathology; Permeability; Pharmacology; Physiological; Physiology; Play; Process; Proteins; Rattus; Receptor Signaling; Recombinants; Role; Schizophrenia; Shaken baby syndrome; Shapes; Signal Pathway; Signal Transduction; Site; Spinal Cord; Spinal cord injury; Sports; Stimulus; Stroke; Synapses; Testing; Therapeutic; Traumatic Brain Injury; Work; addiction; biophysical properties; cell type; chronic pain; combat; design; experience; experimental study; in vivo; mechanical force; mechanical properties; nervous system disorder; neuropathology; neurotransmission; novel; novel therapeutic intervention; patch clamp; programs; receptor; response; severe psychiatric disorder; synaptic function; synaptogenesis; tumor; voltage

Project Summary/Abstract In the central nervous system, proteins experience mechanical cues that vary widely across developmental stage, cell type and location, and physiological state. When acting on membrane embedded ion-channel proteins, mechanical forces can modulate the ionic flux produced by the physiological activator or can directly gate the channel. In this application, we explore the hypothesis that mechanical forces can open NMDA receptors in the absence of the endogenous neurotransmitter glutamate. NMDA receptors are glutamate-gated excitatory receptors that are widely expressed at synaptic and extrasynaptic sites in brain and spinal cord, where they play key roles in physiology and pathology of excitatory synaptic development and plasticity. These key functions rely on unique biophysical properties such as, among others, slow kinetics, large calcium permeability, voltage-dependent Mg2+ block. In this application, we propose to pursue two interrelated aims. The first will be done in recombinant receptors and will examine the type and intensity of force that can gate the channel, the biophysical properties of the force-induced current (kinetics, conductance, permeability, etc.), and how the channel senses the mechanical cue. The second aim will be done in endogenous receptors (primary cultured neurons) and will begin to explore possible roles of mechanically gated NMDA receptor currents in physiologic and pathologic conditions. In both aims, we will use electrophysiology and optical methods to monitor NMDA receptor response, total and calcium current, to experimentally-controlled mechanical perturbations. These experiments will delineate what kind of mechanical forces can activate NMDA receptors and how the signals produced by force and by glutamate compare, and will help to predict the physiological and pathological situations where mechanical forces can shape neuronal function specifically by gating NMDA receptor currents. Given that the mechanosensitivity of NMDA receptor signals is yet uncharted, the results will lay the groundwork necessary to understand how NMDA receptors contribute to the impact of mechanical forces on synaptic function and dysfunction.

项目总结/摘要 在中枢神经系统中，蛋白质经历的机械线索在发育过程中变化很大。 阶段、细胞类型和位置以及生理状态。作用于膜包埋离子通道时 蛋白质，机械力可以调节由生理激活剂产生的离子通量，或者可以直接 打开通道在本应用中，我们探索了机械力可以打开NMDA的假设 受体的内源性神经递质谷氨酸的情况下。 NMDA受体是谷氨酸门控兴奋性受体，其广泛表达于突触和突触后膜。 突触外部位的大脑和脊髓，在那里他们发挥关键作用的生理和病理兴奋性 突触发育和可塑性。这些关键功能依赖于独特的生物物理特性，例如， 其他的，动力学缓慢，大的钙渗透性，电压依赖性Mg ~（2+）阻滞。在本申请中，我们提出 追求两个相互关联的目标。第一个将在重组受体中进行，并将检查类型和 可以门控通道的力的强度，力诱导电流的生物物理性质（动力学， 电导率、渗透率等），以及通道如何感知机械提示。第二个目标是 在内源性受体（原代培养的神经元）中完成，并将开始探索 机械门控NMDA受体电流的生理和病理条件。在这两个目标中，我们将使用 电生理学和光学方法监测NMDA受体反应，总电流和钙电流， 实验控制的机械扰动。 这些实验将阐明什么样的机械力可以激活NMDA受体，以及如何激活NMDA受体。 由力和谷氨酸产生的信号比较，将有助于预测生理和 机械力可以通过门控NMDA特异性地塑造神经元功能的病理情况 受体电流。考虑到NMDA受体信号的机械敏感性尚未被绘制，结果将 奠定必要的基础，了解NMDA受体如何有助于机械的影响， 对突触功能和功能障碍的影响。