Modulation of Olfactory Bulb Neuron Current Properties

嗅球神经元电流特性的调节

• 批准号: 7707368
• 负责人: DEBRA Ann FADOOL
• 金额: $ 2.94万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707368
• 关键词: Adaptor Signaling Protein; Alzheimer' s Disease; Axon; Behavioral; Biochemical; Cell Communication; Cell Proliferation; Cells; Co-Immunoprecipitations; Complex; Cytoplasmic Granules; Cytoplasmic Protein; DLG4 gene; Diabetes Mellitus; Differentiation and Growth; Disease; Electric Stimulation; Electrophysiology (science); Embryo; Environment; Enzymes; Gene Targeting; Growth; Growth Factor; Human; Infusion procedures; Insulin Receptor; Ion Channel; Knockout Mice; Kv1.3 potassium channel; Link; Malignant Neoplasms; Measurement; Measures; Modeling; Molecular; Mouse Strains; Mus; Mutagenesis; Neuromodulator; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Neurotrophin 3; PTB Domain; Pattern; Phosphorylation; Phosphotransferases; Physiological; Plastics; Potassium; Potassium Channel; Process; Property; Protein Kinase; Protein phosphatase; Proteins; Receptor Protein-Tyrosine Kinases; Research; Research Design; Role; Sensory; Severities; Signal Transduction; Signaling Molecule; Signaling Protein; Site-Directed Mutagenesis; Slice; Smell Perception; Synapses; System; Tyrosine; Tyrosine Phosphorylation; Work; base; experience; insulin receptor tyrosine kinase; kidney cell; loss of function; multidisciplinary; neural circuit; neuroregulation; neurotrophic factor; olfactory bulb; olfactory receptor; patch clamp; protein protein interaction; receptor; regenerative; research study; scaffold

DESCRIPTION (provided by applicant): The designed research is a multidisciplinary analysis of the modulation of potassium currents in granule and mitral cells of the olfactory bulb. The broad, long-term objective of this research is to elucidate how neurotrophins and growth factors can utilize ion channels as substrates for phosphorylation to give rise to short-term and long-term plastic changes in synaptic efficacy or to aid in the establishment of neural circuits in the olfactory bulb. Understanding the general principles governing these transduction cascades and the involvement of ion channels will provide information of how protein kinases and protein phosphatases contribute to the onset or severity of specific neuronal diseases, such as Alzheimer's, or how uncontrolled signaling of these enzymes leads to deregulated cell proliferation and diseases such as cancer and diabetes. Because of the unique trophic and regenerative capacity of neurons in the olfactory system, continual expression of neuromodulators could alter patterns of electrical excitability in addition to their well-studied roles in growth and differentiation. The specific aims of this proposal are to characterize using patch-clamp electrophysiology how receptor-linked tyrosine phosphorylation signaling in the olfactory bulb is altered by sensory experience, patterned electrical stimulation, and trophic factor infusion. By utilizing the cloned, olfactory bulb potassium channel Kv1.3 as a parallel model, combined biochemical measurement of kinase-induced tyrosine phosphorylation, co-immunoprecipitation, and molecular mutagenesis will elucidate the mechanistic details of how ion channels form molecular scaffolds with kinases and adaptor proteins through discrete protein-protein interactions at SH2, SH3, PDZ, and PTB domains. Gene-targeted deletions in Kv1.3 channel, insulin receptor kinase, and TrkB kinase will provide mechanistic details for the role for tyrosine phosphorylation signaling in olfaction and for neuromodulation in the CNS in general, as defined by loss of function experiments (behavioral, biochemical, electrophysiological) using knock-out mice strains. The proposal will provide new important information regarding the integration of signaling molecules by construction of protein-protein interactions with ion channels. Modulation of ion channel function would thus be dependent upon the repertoire of signaling proteins expressed in a given neuron, a background that could change with sensory experience or electrical patterning.

描述(申请人提供)：设计的研究是对嗅球颗粒细胞和二尖瓣细胞钾电流调制的多学科分析。这项研究的长期目标是阐明神经营养素和生长因子如何利用离子通道作为底物进行磷酸化，从而引起突触效率的短期和长期可塑性变化，或者帮助建立嗅球的神经回路。了解这些转导级联的一般原理和离子通道的参与，将提供关于蛋白激酶和蛋白磷酸酶如何在特定神经元疾病(如阿尔茨海默氏病)的发生或严重程度中起作用的信息，或者这些酶的不受控制的信号如何导致细胞增殖和癌症和糖尿病等疾病的失控。由于神经元在嗅觉系统中具有独特的营养和再生能力，神经调节剂的持续表达除了在生长和分化中的作用外，还可以改变电兴奋的模式。这项建议的具体目的是利用膜片钳电生理学来表征嗅球中受体连接的酪氨酸磷酸化信号是如何随着感觉体验、模式电刺激和营养因子的注入而改变的。通过利用克隆的嗅球K+通道Kv1.3作为平行模型，结合激酶诱导的酪氨酸磷酸化、免疫共沉淀和分子突变的生化检测，将阐明离子通道如何通过SH2、SH3、PDZ和PTB结构域上离散的蛋白质-蛋白质相互作用与激酶和接头蛋白形成分子支架的机制细节。Kv1.3通道、胰岛素受体激酶和TrkB激酶中的基因靶向缺失将提供酪氨酸磷酸化信号在嗅觉中的作用以及一般中枢神经系统神经调节的机制细节，这是通过使用基因敲除小鼠品系进行的功能丧失实验(行为、生化、电生理)所定义的。该提案将提供有关通过构建与离子通道的蛋白质-蛋白质相互作用来整合信号分子的新的重要信息。因此，离子通道功能的调节将依赖于在给定神经元中表达的信号蛋白的谱系，这一背景可能会随着感觉经验或电模式的变化而改变。