G protein-gated K+ channels and inhibitory signaling

描述：我研究的长期目标是了解G是如何 蛋白门控钾通道(GIRK或KG通道)参与抑制 整个中枢神经系统的信号，以及细胞如何 KG功能的后果转化为建立或修改 复杂的行为，如痛觉、成瘾、学习和记忆。 Kg通道由GIRK成员的异多聚体组装而成 通道子单元家族。哺乳动物的四个GIRK亚基分布于 遍及中枢神经系统、心脏、胰腺和睾丸。而当 KG通道神经递质激活对心功能的重要性 众所周知，对它们在抑制中的作用知之甚少。 中枢神经系统中的信号和行为调整。这项工作 本提案中的详细信息旨在揭示KG渠道如何与 其他G蛋白偶联效应器在大脑中引起突触抑制。 然而，首先，将付出相当大的努力来准确地划定 其中每个GIRK亚基在大脑中表达。GIRK mRNAs将本地化 在小鼠中枢神经系统中进行原位杂交。一本小说 将使用转基因策略来补充和扩展本地化 通过揭示GIRK3亚基蛋白在 亚细胞水平。此外，其潜在的分子机制 将探索分布。我们还将评估KG的贡献 通道和其他离子电流对阿片类药物急性和慢性影响 蓝斑。目前，该领域对以下问题存在分歧： KG对阿片类药物在蓝斑急性效应中的作用。 此外，我们对慢性影响潜在机制的理解 阿片类药物的使用(耐受性)是不完整的。缺乏KG的小鼠 蓝斑将被用来填补我们知识中的这些空白。完成 这项工作将是通向全面理解的第一步 中枢神经系统中神经递质对KG的调节。在……里面 此外，它将为评估这一特殊情况的影响提供基础。 离子通道类在细胞和整个动物中的各种行为 级别。

DESCRIPTION: The long-term goal of my research is to understand how G protein-gated potassium channels (GIRK or KG channels) contribute to inhibitory signaling throughout the central nervous system, and how the cellular consequences of KG function translate into the establishment or modification of complex behaviors such as pain perception, addiction, and learning and memory. KG channels are formed by heteromultimeric assembly of members of the GIRK channel subunit family. The four mammalian GIRK subunits are distributed throughout the central nervous system, heart, pancreas, and testis. While the importance of neurotransmitter activation of KG channels to cardiac function is well understood, little is known regarding their contribution to inhibitory signaling and behavioral modification in the central nervous system. The work detailed in this proposal seeks to reveal how KG channels work in concert with other G protein-coupled effectors to elicit synaptic inhibition in the brain. First, however, considerable effort will be devoted to delineating precisely where each GIRK subunit is expressed in the brain. GIRK mRNAs will be localized in the mouse central nervous system by in situ hybridization. A novel transgenic strategy will be used to complement and extend the localization studies by revealing the distribution of the GIRK3 subunit proteins at the subcellular level. In addition, potential molecular mechanisms underlying their distribution will be explored. We will also evaluate the contribution of KG channels and other ion currents to the acute and chronic effects of opiates in the locus coeruleus. Currently, there is disagreement in the field concerning the contribution of KG to the acute effects of opiates in the locus coeruleus. In addition, our understanding of the mechanisms underlying the chronic effects of opiate administration (tolerance) is incomplete. Mice lacking KG in the locus coeruleus will be used to address these gaps in our knowledge. Completion of this work will constitute a first step toward a comprehensive understanding of KG regulation by neurotransmitters in the central nervous system. In addition, it will provide a basis for evaluating the impact of this particular ion channel class on a variety of behaviors at the cellular and whole-animal levels.