MOLECULAR MECHANISMS OF GLUTAMATE RECEPTOR CHANNELS

这项研究的长期目标是通过以下方式了解机制： 大脑中的哪些突触会因活动和环境而改变 刺激。 我们专注于一种特殊类型的突触受体-NMDA 一类谷氨酸受体-在长期的 突触功能的变化，细胞死亡的调节， 在神经元网络中产生模式化的活动。 这些过程 需要NMDA受体允许适量的钙 离子通过它的孔，进入神经元，并被阻止， 细胞外镁离子在适当范围的膜 潜力和浓度。 因此，为了理解 突触可塑性的分子基础，我们必须了解 确定二价阳离子渗透性和阻断的机制 NMDA受体。 我们将使用重组DNA技术来证明 受体蛋白的突变，然后研究改变的功能， 突变受体（在卵母细胞中表达）的单通道贴片 钳位法 我们将研究如何孔残留物， 受体的亚基组成，决定对钙的亲和力 和镁，如果通道电导由静电调节， 机制，以及亚电导水平的机制 生成的. 我们还将研究亚基组成（类型和 拷贝数）的受体通过研究模式的亚电导 状态是明显的受体组成的不同混合物， 野生型和突变亚基。 对分子的理解 NMDA受体通道的运作机制将提供深入了解 发展的基础，退化和其他疾病的 神经系统

The long term goal of this research is to understand the mechanisms by which synapses in the brain are changed by activity and environmental stimuli. We focus on a specific type of synaptic receptor - the NMDA class of glutamate receptor - that plays an important role in long-term changes in synaptic function, the regulation of cell-death, and the generation of patterned activity in neuronal networks. These processes require that the NMDA receptors allow the appropriate amount of calcium ion to pass through its pore and enter the neuron, and be blocked by extracellular magnesium ion over an appropriate range of membrane potentials and concentrations. Thus, in order to understand the molecular bases of synaptic plasticity, we must understand the mechanisms that determine the divalent cation permeability and block of NMDA receptors. We will use recombinant DNA technology to make point mutations in the receptor protein, and then study the altered functions of mutant receptors (expressed in oocytes) using single-channel patch clamp methods. We will investigate how the pore residues, and the subunit composition of the receptor, determine the affinity for calcium and magnesium, if the channel conductance is regulated by electrostatic mechanisms, and the mechanisms by which subconductance levels are generated. We will also investigate the subunit composition (type and copy number) of receptors by studying the patterns of subconductance states that are apparent in receptors composed of different mixtures of wild type and mutant subunits. An understanding of the molecular mechanisms of operation of NMDA receptors channels will provide insight into the basis of developmental, degenerative and other diseases of the nervous system.