NEUROMODULATION OF ION CHANNELS

神经生物学家面临的一个核心挑战是理解 细胞和分子的机制，产生了持久的 行为的改变，如学习和记忆。 这 对于任何脊椎动物神经元， 系统，但目前的学习模式调用使用依赖 神经元电特性的改变，特别是在 突触 因为离子通道是细胞的基本结构 阻断了可兴奋细胞中所有电信号的基础， 对神经元可塑性的理解必须包括以下信息： 离子通道的特性如何被这些 信号分子 本建议的总体方针是 确定离子通道可以 响应并整合多个信令承载的信息， 分子。 这种整合机制被认为是一种 神经可塑性表达的重要组成部分， 赋予神经元独特的反应能力 环境 Ca2+激活的钾离子（Kca）通道是一种 特别有用和通用的模型来研究信号集成 因为它们可以被许多细胞内的 信号分子，这些通道在大多数（如果不是全部的话） 神经元在两个细胞体和突触，他们有一个大的 促进电生理记录的单一电导。 我们 将结合电生理学，分子生物学， 和生物化学方法来确定钙离子和蛋白质 激酶调节人Kca通道，并测试这些 通道可以整合多种信号通路， 分子符合探测器 处理的具体问题 该建议是1。 细胞内Ca2+的升高 被KCA通道感知并转化为通道开放？2. 多种蛋白激酶的作用是如何翻译成K Ca 通道开放？，Kca通道能否作为分子通道发挥作用 符合探测器，其对同时发生的 激活两个或两个以上的信号通路？ 我们的结果将 提供了离子通道可以 作为符合探测器，因此提供有关 神经可塑性的分子基础这些信息提供了 理解高阶过程的基础，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.