The Role of DPP6 in Kv4 Localization and Dendritic Excitability

DPP6 在 Kv4 定位和树突兴奋性中的作用

• 批准号: 8003307
• 负责人: Jonathon K Maffie
• 金额: $ 4.45万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003307
• 关键词: Action Potentials; Apical; Back; Complex; Dendrites; Distal; Employee Strikes; Exhibits; Family; Generations; Grant; Heart; Hippocampus (Brain); Individual; Invaded; Kv4 channel; Kv4.2 channel; Mediating; Membrane Potentials; Molecular; Mus; Neurons; Pattern; Potassium; Potassium Channel; Proteins; Pyramidal Cells; Role; Signal Transduction; Synapses; Synaptic plasticity; Testing; Time; Trees; Work; attenuation; computerized data processing; electrical property; hippocampal pyramidal neuron; public health relevance; research study

DESCRIPTION (provided by applicant): The large diversity of Potassium (K+) channels is a critical determinant to the great variety of electrical properties exhibited by neurons. One such family of potassium channels, the Kv4 family, mediates transient (fast-inactivating) currents which activate at subthreshold membrane potentials and are found in the somatic and dendritic compartments of neurons. This current is referred to as A-type current or ISA in neurons and ITO in the heart. Kv4 channels are thought to be ternary complexes composed of a tetramer of pore forming (Kv4) subunits together with KChIP intracellular auxiliary subunits and DPP-like (DPP6 or DPP10) auxiliary subunits. Kv4 channels have been shown to display complex, dynamic subcellular localization in neurons. This highly specific distribution is crucial to the dendrite's ability to perform several basic functions. These basic signal processing functions include: attenuation of the back propagating action potential, scaling synaptic inputs, modulating individual branch excitability. Kv4 channels are present in a striking gradient along the apical dendrite of hippocampal pyramidal neurons with a higher concentration in the distal dendrite and relatively low perisomatic concentration. This concentration gradient is responsible for the attenuation of the back propagation of the action potential as it invades the dendritic tree, with important consequences for spike-timed dependent synaptic plasticity. It also serves as the signal for proper dendritic scaling along the apical dendrite. However, the molecular determinants of this important gradient are not known. I have been working with DPP6 KO mice to study the role of the auxiliary subunit DPP6 in native neurons, focusing on hippocampal CA1 pyramidal cells. I have obtained exciting preliminary evidence suggesting that DPP6 is necessary for the establishment of the Kv4 channel somato-dendritic gradient. These experiments suggest that the absence of DPP6 causes a redistribution of Kv4 channels including a loss of the somato- dendritic gradient. In this grant I will pursue these preliminary observations to test the hypothesis that DPP6 is an important molecular component of Kv4 channels in neurons that determines its somato-dendritic expression pattern and I will investigate the consequences of DPP6 loss to the cellular and dendritic excitability and generation of synaptic plasticity. PUBLIC HEALTH RELEVANCE: The specific subcellular distribution pattern of Kv4.2 is crucial to Hippocampal CA1 Pyramidal cell dendrite's ability to perform several basic functions. In this grant I will pursue preliminary observations that in the absence of DPP6, a protein that associates with Kv4.2 channels, the subcellular distribution pattern of Kv4.2 is lost. To test the hypothesis that DPP6 is an important molecular component of Kv4 channels in neurons that determines its somato-dendritic expression pattern I will investigate the consequences of DPP6 loss to the cellular and dendritic excitability and generation of synaptic plasticity.)

描述（由申请人提供）：钾 (K+) 通道的多样性是神经元表现出的多种电特性的关键决定因素。 Kv4 家族就是这样的钾通道家族之一，它介导瞬时（快速失活）电流，该电流在阈下膜电位下激活，存在于神经元的体细胞和树突区室中。该电流在神经元中称为 A 型电流或 ISA，在心脏中称为 ITO。 Kv4 通道被认为是由成孔 (Kv4) 亚基四聚体与 KChIP 细胞内辅助亚基和 DPP 样（DPP6 或 DPP10）辅助亚基组成的三元复合物。 Kv4 通道已被证明在神经元中表现出复杂、动态的亚细胞定位。这种高度特异性的分布对于树突执行多种基本功能的能力至关重要。这些基本信号处理功能包括：反向传播动作电位的衰减、缩放突触输入、调节各个分支的兴奋性。 Kv4 通道沿海马锥体神经元顶端树突呈显着梯度，远端树突浓度较高，体周浓度相对较低。这种浓度梯度导致动作电位侵入树突树时反向传播的衰减，对尖峰时间依赖性突触可塑性产生重要影响。它还充当沿着顶端树突进行适当树突缩放的信号。然而，这一重要梯度的分子决定因素尚不清楚。我一直在用 DPP6 KO 小鼠研究辅助亚基 DPP6 在天然神经元中的作用，重点关注海马 CA1 锥体细胞。我获得了令人兴奋的初步证据，表明 DPP6 对于 Kv4 通道体细胞树突梯度的建立是必需的。这些实验表明，DPP6 的缺失会导致 Kv4 通道的重新分布，包括体细胞树突梯度的损失。在这笔资助中，我将进行这些初步观察，以检验以下假设：DPP6 是神经元 Kv4 通道的重要分子成分，决定其体细胞树突表达模式，并且我将研究 DPP6 损失对细胞和树突兴奋性和生成的影响突触可塑性。 公共健康相关性：Kv4.2 的特定亚细胞分布模式对于海马 CA1 锥体细胞树突执行多种基本功能的能力至关重要。在这笔资助中，我将进行初步观察，即在缺乏 DPP6（一种与 Kv4.2 通道相关的蛋白质）的情况下，Kv4.2 的亚细胞分布模式会丢失。为了检验 DPP6 是神经元 Kv4 通道的重要分子成分（决定其体细胞树突表达模式）的假设，我将研究 DPP6 损失对细胞和树突兴奋性以及突触可塑性产生的影响。）