ARE SODIUM-ACTIVATED POTASSIUM CHANNELS THE "GATE-KEEPERS" OF SYNAPTIC INTEGRATION?

钠激活钾通道是突触整合的“看门人”吗？

• 批准号: 8951969
• 负责人: LAWRENCE B SALKOFF
• 金额: $ 19.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8951969
• 关键词: Action Potentials; Affect; Antibiotics; Area; Axon; Behavior; Brain; Cell membrane; Cells; Complex; Disease; Down-Regulation; Frequencies; Generations; Goals; Image; Individual; Interphase Cell; Ions; Learning; Letters; Measures; Membrane; Membrane Potentials; Memory; Memory Loss; Nervous system structure; Neuromodulator; Neurons; Nystatin; Optical Methods; Potassium Channel; Property; Pyramidal Cells; Relative (related person); Second Messenger Systems; Senile dementia; Shapes; Signal Pathway; Signal Transduction; Site; Sodium; Synapses; Synaptic Potentials; Syndrome; Techniques; Testing; Xenopus oocyte; electrical property; mitral cell; neuronal cell body; neuronal excitability; neuroregulation; olfactory bulb; patch clamp; public health relevance; research study; second messenger; voltage; voltage clamp

 DESCRIPTION (provided by applicant): This proposal tests the hypothesis that the unusual sodium-activated K+ current controls synaptic integration in an unanticipated way which is widespread in the mammalian brain. As such, it may be a previously unrecognized factor in memory and learning. Sodium-activated K+ channels (KNa channels) are present in most areas of the brain and are prevalent in the cell bodies of many pyramidal cells. In mitral cells of the olfactory bulb, KNa channels are densely packed into the plasma membrane of the cell body. In mitral cells, the cell body is interposed between the dendritic tuft which inputs synaptic potentials and the axon initial segment which is one site of action potential initiation in these cells. If KNa channels in the cell body were constitutively active, incoming synaptic potentials from the glomerulus would be shunted by the high K+ conductance of the soma, never reaching the axon spike initiation zone. However, we have shown by heterologous expression that KNa channels are highly modulated by metabotropic signaling through the G-alphaQ signaling pathway. If similarly modulated in mitral and other cells, their activity could be largely blocked r unblocked by metabotropic signaling at the soma. Thus, KNa channels may be "gate-keepers" of synaptic integration in the olfactory bulb where they could either block or permit the generation of action potentials by incoming synaptic potentials. This proposal aims to test the hypothesis that (1) KNa channels present in the cell bodies of mitral cells are indeed regulated by metabotropic signaling and (2) KNa channels must be down-regulated to permit the cell to generate an action potential. KNa channels are found in the plasma membrane of neuronal soma throughout the nervous system and could well be an important factor governing the intrinsic excitability of many cells; the intrinsic excitability of a neuron is increasingly undersood to be an important factor in synaptic integration and plasticity, and may be an important non-synaptic factor in memory and learning. These studies may provide a better understanding and treatment of disease which leads to deficits in learning and memory loss, such as the multiple syndromes producing senile dementia.

 描述（由申请人提供）：该提案测试了这样的假设：不寻常的钠激活 K+ 电流以一种意想不到的方式控制突触整合，这种方式在哺乳动物大脑中广泛存在，因此它可能是记忆和学习中以前未被认识的因素。钠激活的 K+ 通道（KNa 通道）存在于大脑的大部分区域，并且普遍存在于许多锥体细胞的细胞体中。在嗅球的二尖瓣细胞中，KNa 普遍存在。通道密集地分布在细胞体的质膜中，细胞体介于输入突触电位的树突簇和轴突起始段之间，轴突起始段是这些细胞中动作电位起始的位点之一。细胞体内的突触电位是组成性活跃的，来自肾小球的传入突触电位将被胞体的高 K+ 电导分流，永远不会到达轴突尖峰起始区。然而，我们通过异源表达表明，KNa 通道通过 G-alphaQ 信号通路受到代谢信号的高度调节，如果在二尖瓣和其他细胞中进行类似的调节，它们的活性可能会在很大程度上被体细胞的代谢信号阻断。 KNa 通道可能是嗅球中突触整合的“看门人”，它们可以阻止或允许传入突触电位产生动作电位。假设 (1) 二尖瓣细胞细胞体中存在的 KNa 通道确实受到代谢信号的调节，(2) KNa 通道必须下调才能允许细胞在质膜中发现动作电位。神经元的内在兴奋性越来越被认为是突触整合和可塑性的重要因素，并且可能是控制许多细胞内在兴奋性的重要因素；这些研究可能有助于更好地理解和治疗导致学习缺陷和记忆丧失的疾病，例如导致老年痴呆症的多种综合征。