Ion Channel Pharmacology for Pain and Epilepsy

项目总结/摘要 拟议的工作将整合实验室两个长期存在的研究领域。一是 理解是理解在单个神经元中存在的多种离子通道 共同调节它的放电模式在早期的资助阶段， 门控行为和各种钙通道，钠通道， 不同种类的哺乳动物神经元中的钾通道。最近，我们试图 了解电流如何通过给定神经元类型中的多种通道 相互作用，通常以令人惊讶的方式，控制神经元的放电模式。在第二行 研究，我们已经确定了各种药理学药物的特点，这些药物的目标是 电压依赖性通道这项工作的大部分最初集中在寻找肽毒素， 用于分离来自特定通道类型的电流成分的小分子。我们 现在的目标是利用我们不断扩展的关于离子通道组成差异的知识， 不同种类的神经元，以合理地设计新的化合物，可以抑制（或增强） 特定种类神经元的活动。假设很多临床上的- 有效的药物作用于多个离子通道，我们将尝试设计单一的化合物， 故意设计来抑制或增强电压依赖性钠的特定组合， 钾和钙通道，以差异性地抑制（或增强）特定神经元的放电 感兴趣的类型，包括初级伤害感受器，海马和皮质锥体神经元， 皮质和海马GABA能神经元的各种群体，以及脊髓运动神经元的各种群体， 神经元，以设计具有临床有益效果的方式。我们方法的一个关键要素是 意识到几乎所有针对电压依赖性通道的小分子化合物 与通道的不同门控状态有差异地相互作用，导致复杂的 依赖于电压波形。因此，不同神经元类型的差异抑制可以 也基于其不同的静息电位、动作电位形状和放电模式 作为目标的特定信道类型的存在或不存在。我们以往的经验 一系列细胞类型，通道类型和通道靶向药物将提供强大的 这一努力的基础。

Project Summary/ Abstract The proposed work will integrate two long-standing lines of research in the laboratory. One is to understand is to understand how the many types of ion channels present in a single neuron work together to regulate its firing pattern. In earlier grant periods, we focused on the individual gating behavior and functional roles of various kinds of calcium channels, sodium channels, and potassium channels in different kinds of mammalian neurons. More recently, we have tried to understand how the currents through the many kinds of channels in a given neuronal type interact, often in surprising ways, to control the firing pattern of the neuron. In a second line of research, we have characterized a variety of pharmacological agents that are targeted to voltage-dependent channels. Much of this work originally focused on finding peptide toxins and small molecules useful for separating components of current from specific channel types. Our goal now is to use our expanding knowledge about the differences in ion channel make-up of different kinds of neurons to rationally design novel compounds that can inhibit (or enhance) activity of specific kinds of neurons. Hypothesizing that it is no accident that many clinically- effective drugs act on multiple ion channels, we will attempt to design single compounds deliberately designed to inhibit or enhance specific combinations of voltage-dependent sodium, potassium, and calcium channels to differentially depress (or enhance) firing of specific neuronal types of interest, including primary nociceptors, hippocampal and cortical pyramidal neurons, various populations of cortical and hippocampal GABAergic neurons, and spinal cord motor neurons, in ways designed to have clinically beneficial effects. A key element of our approach is realizing that almost all small-molecule compounds targeted to voltage-dependent channels interact differentially with different gating states of the channels, resulting in complex dependence on voltage waveforms. Thus, differential inhibition of different neuronal types can be based on their different resting potentials, action potential shapes, and firing patterns as well as presence or absence of particular channel types being targeted. Our previous experience with a range of cell types, channel types, and channel-targeted drugs will provide a strong foundation for this effort.