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: 9087358
• 负责人: LAWRENCE B SALKOFF
• 金额: $ 22.88万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087358
• 关键词: Action Potentials; Affect; Antibiotics; Area; Axon; Behavior; Brain; Cell membrane; Cells; Complex; Disease; Down-Regulation; Frequencies; Generations; Goals; Health; 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; 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; 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(申请人提供)：这项建议测试了一种假设，即不寻常的钠激活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的大脑中广泛存在。因此，它可能是记忆和学习中一个以前未被认识到的因素。钠激活的K+通道(KNA通道)存在于大脑的大部分区域，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通道密集地堆积在细胞体的质膜中。在二尖瓣细胞中，细胞体位于输入突触电位的树突束和轴突起始段之间，轴突起始段是这些细胞中动作电位的起始点之一。如果细胞体中的KNA通道是结构性激活的，来自肾小球的突触电位将被胞体的高K+电导分流，永远不会到达轴突棘波起始区。然而，我们通过异源表达表明，KNA通道通过G-AlphaQ信号通路受到代谢性信号的高度调制。如果在二尖瓣和其他细胞中进行类似的调节，它们的活动可能在很大程度上被胞体的代谢性信号阻断或解除阻断。因此，KNA通道可能是嗅球突触整合的“守门人”，它们可以阻断或允许传入突触电位产生动作电位。这一建议旨在验证这样的假设：(1)存在于二尖瓣细胞胞体中的KNA通道确实受到代谢性信号的调节，(2)KNA通道必须下调以允许细胞产生动作电位。KNA通道广泛存在于神经系统神经元胞体的质膜上，可能是控制许多细胞内在兴奋性的重要因素；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，也可能是记忆和学习中重要的非突触因素。这些研究可能提供对导致学习和记忆丧失的疾病的更好的理解和治疗，例如导致老年痴呆症的多种综合征。