NEUROMODULATION OF ION CHANNELS

神经生物学家面临的主要挑战之一是理解 导致长效的细胞和分子机制 行为的改变，如学习和记忆。这 对于任何脊椎动物神经元来说，还没有意识到挑战 系统，但当前的学习模型依赖于使用 神经元电学特性的改变，尤其是在 突触。因为离子通道是基础建筑 阻断所有可兴奋细胞中的电信号，任何 对神经元可塑性的理解必须包括以下信息 离子通道的性质如何通过这些来调节 信号分子。这项建议的总体方针是 确定离子通道的分子机制 响应并整合由多个信令携带的信息 分子。这种综合机制被认为是一种 神经可塑性表达的重要组成部分，以及 赋予神经元对变化的独特反应的能力 环境。Ca2plus激活的Kplus(KCA)通道是 对研究信号集成特别有用和通用的模型 因为它们可以被许多细胞内的 信号分子，通道在大多数(如果不是全部)中表达 在细胞体和突触中的神经元，它们有一个很大的 便于电生理记录的单一电导。我们 将使用电生理学、分子生物学、 以及生化方法来确定钙离子和蛋白质如何 激酶调节人的KCA通道，并测试这些 通道可以集成多个信号通路来发挥作用 分子符合探测器。解决的具体问题 这一建议是1.细胞内钙离子的升高是如何 KCA通道感知并转化为通道开放？，2. 多种蛋白激酶在K细胞中的作用如何 通道开放？和2，KCA通道能否作为分子发挥作用 唯一响应同步信号的符合探测器 激活两条或更多条信号通路？我们的结果将 提供有关离子通道可 充当符合探测器，因此提供有关 神经可塑性的分子基础。这些信息提供了 了解高阶过程的基础，如学习和 记忆。

One of the central challenges facing neurobiologists is to understand the cellular and molecular mechanisms that give rise to long-lasting alterations in behavior, such as learning and memory. This challenge has not yet been realized for any vertebrate neuronal system, but current models of learning invoke use-dependent alterations in the electrical properties of neurons, particularly at synapses. Because ion channels are the fundamental building blocks underlying all electrical signaling in excitable cells, any understanding of neuronal plasticity must include information about how the properties of ion channels can be modulated by these signaling molecules. The overall approach of this proposal is to determine the molecular mechanisms by which ion channels can respond to and integrate information carried by a multiple signaling molecules. Such integrative mechanisms are believed to be an important component in the expression of neuroplasticity, and endow neurons with the ability to respond uniquely to a changing environment. Ca2plus -activated Kplus (Kca) channels are a particularly useful and general model to study signal integration because they can be modulated by a number of intracellular signaling molecules, the channels are expressed in most if not all neurons in both cell bodies and at synapses, and they have a large unitary conductance facilitating electrophysiological recordings. We will use a combination of electrophysiological, molecular biological, and biochemical approaches to determine how ca2plus and protein kinases modulate human Kca channels, and test whether these channels can integrate multiple signaling pathways to function as molecular coincidence detectors. Specific questions addressed by this proposal are 1. How is an elevation in intracellular Ca2plus sensed and translated into channel opening by Kca channels?, 2. How are the effects of multiple protein kinases translated into K ca channel opening?, and 2, Can Kca channels function as molecular coincidence detectors that respond uniquely to the simultaneous activation of two or more signaling pathways? Our results will provide information on the mechanisms by which ion channels can act as coincidence detectors, and hence provide information on the molecular basis of neuroplasticity. Such information provides the basis for understanding higher order process such as learning and memory.