NON-NMDA RECEPTORS & CALCIUM CHANNELS IN NEURONS

脊髓背角是感觉传入的重要部位 传递到中央神经元。 突触之间的相互作用 受体和电压门控钙通道（VGCC），以及它们的组合 对Ca 2+内流的影响尚未在背角神经元或 在中枢神经系统的其他地方。 然而， [Ca2+] i和钙驱动的膜电位变化可能具有 对周围刺激的感觉产生深远的影响， 和病理状态。 初级突触之间的快速突触传递 传入神经及其背角靶点主要涉及兴奋性 谷氨酸递质，作用于一个或多个突触家族 兴奋性氨基酸（EAA）受体，称为NMDA，和非NMDA或 红藻氨酸和使君子酸受体。 EAA将通过以下方式对细胞进行脱乙酰化： 激活这些受体并间接激活VGCC，引起[Ca2 +] i 从而提高膜电位，使其去极化程度更高。 这种形式的 相互作用意味着突触激活的钙依赖性电位与 膜电位变化和膜电位变化的高度非线性增强， [Ca2+] i. 最近的实验也表明，红藻氨酸激活 存在可渗透Ca 2+的受体操纵通道（ROCs）。 如果这些在 背角神经元的定位、动力学改变 和突触激活过程中Ca~（2+）内流的电压依赖性。 最后， 代谢偶联的非NMDA受体具有 在背角神经元中的突触传递中的作用还未被测试。 因此，将在非NMDA后研究Ca2+内流的调节 受体激活以确定1）Ca2+是否通过非NMDA进入 受体发生，2）VGCC特性的贡献，以确定 诱发的[Ca2 +] i瞬变的幅度和时程; 3） 非NMDA受体介导的[Ca~（2+）] i变化中Ca~（2+）释放的变化。 同时测量[Ca2 +] i和膜电位变化应 特别是关于Ca2+进入是否是由于Ca2 +- 依赖性动作电位或持续开放VGCC。 树突状 受体和通道特性将使用微光视频进行研究 成像具有良好的空间分辨率，光电倍增管具有良好的时间 分辨率 这样的研究将提高我们对复杂的理解 通常发生在突触输入和VGCC之间的相互作用， 背角 此外，[Ca2 +] i的变化也涉及到 突触传递的活动依赖性促进过程， 这可能是异常性疼痛等病理性疼痛综合征的基础。 最后， 由于EAA介导的脊髓神经元[Ca 2 +] i持续升高， 与脊髓损伤后继发性细胞死亡相关 损伤，这些实验可能会提高基本的理解， 与细胞死亡有关的机制。

The dorsal horn of the spinal cord is an important site of afferent sensory transmission to central neurons. Interactions between the synaptic receptors and voltage-gated calcium channels (VGCCs), and their combined effects on Ca2+ entry, have not been well studied in dorsal horn neurons or elsewhere in the central nervous system. Yet the physiological effects of [Ca2+]i and calcium-driven changes in membrane potentials could have profound influence on the sensation of peripheral stimuli in both normal and pathological states. Fast synaptic transmission between primary afferents and their dorsal horn targets primarily involves an excitatory transmitter, glutamate, acting on one or more of a family of synaptic excitatory amino acid (EAA) receptors known as the NMDA, and non-NMDA or kainate and quisqualate receptors. EAAs will depolarize the cells by activation of these receptors and indirectly activate VGCCs causing [Ca2+]i to elevate and membrane potential to become more depolarized. This form of interaction implies synaptic activation of Ca2+-dependent potentials with highly nonlinear boosting of both the change in membrane potential and [Ca2+]i. Recent experiments have also suggested that kainate-activated receptor operated channels (ROCs) permeable to Ca2+ exist. If these are in dorsal horn neurons, it could completely change the localization, kinetics and voltage dependence of Ca2+ entry during synaptic activation. Finally, the possibility of a non-NMDA receptor that is metabolically coupled having a role in synaptic transmission in dorsal horn neurons is untested. Therefore, the regulation of Ca2+ entry will be studied following non-NMDA receptor activation to determine 1) if Ca2+ entry through the non-NMDA receptors occurs, 2) the contribution of VGCC properties to determining the amplitude and time course of the evoked [Ca2+]i transient and 3) the role of Ca2+ release in non-NMDA receptor mediated changes in [Ca2+]i. Simultaneous measurement of [Ca2+]i and membrane potential changes should be particularly informative about whether Ca2+ entry is due to Ca2+- dependent action potentials or sustained opening of VGCCs. Dendritic receptor and channel properties will be studied using low light level video imaging for good spatial resolution and photomultiplier tubes for good time resolution. Such studies will improve our understanding of the complex interactions that normally occur among synaptic inputs and VGCCs in the dorsal horn. Furthermore changes in [Ca2+]i have been implicated in processes of activity dependent facilitation of synaptic transmission such as might underlie pathological pain syndromes like allodynia. Finally, since sustained EAA-mediated elevation of [Ca2+]i in spinal cord neurons is associated with secondary cell death following traumatic spinal cord injury, these experiments may improve the basic understanding of the mechanisms associated with cell death.