Ion channel regulation by heterogeneous membranes

异质膜的离子通道调节

基本信息

批准号：
10473794
负责人：
Sarah L Veatch
金额：
$ 26.08万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473794
关键词：
Behavior Binding Binding Proteins Binding Sites Biochemical Biochemical Process Biophysical Process Brain Cell membrane Cellular Membrane Charge Chemicals Cholesterol Communities Complex Coupling Data Defect Development Disease Electrophysiology (science)Environment Enzymes Fluorescence Goals Health Human Hydrophobicity Image Ion Channel Ions Knowledge Ligands Lipids Liquid substance Measurement Measures Mediating Membrane Mental disorders Microscopy Mission Modeling Molecular Conformation Mutation Nature Nerve Degeneration Neurons Neurosciences Pathologic Pathway interactions Pharmaceutical Preparations Phosphatidylinositols Physical environment Play Post-Translational Protein Processing Process Property Proteins Regulation Regulatory Pathway Research Resolution Rest Role Site Sorting - Cell Movement Structure Synapses Synaptic plasticity Techniques Testing Theoretical model Thermodynamics Tyrosine Phosphorylation United States National Institutes of Health Work addiction effective therapy experience experimental study genetic regulatory protein innovation insight membrane model molecular scale nervous system disorder neurosteroids novel novel strategies novel therapeutic intervention palmitoylation predictive modeling prevent relating to nervous system simulation small molecule stem synaptic function theories treatment strategy voltage

项目摘要

Ion channels are membrane bound proteins that mediate fast neural dynamics by selectively controlling the flow of charged ions across membranes. Most channels are embedded within compositionally complex neuronal membranes, whose detailed composition play important roles in regulating channel functions. Membranes can regulate channels directly, through the binding of specific components to sites within channel structures, or indirectly, by impacting the biophysical and biochemical processes evolved to regulate channel functions in their native environment. A mechanistic understanding of how membrane composition impacts channel functions is vital because changes in neuronal membrane composition are associated with normal development and neurological disease. The goal of the proposed studies is to test three distinct mechanisms through which compositionally complex membranes regulate channel function. The working hypothesis, supported by past collaborative work of the Pl and Col, is that some channel functions are regulated by emergent properties of their embedding membranes that occur because these membranes are heterogeneous. Guided by extensive preliminary data, three specific aims will be pursued: 1) Measure the functional coupling of channel states to membrane domains, 2) Establish how membrane domains impact the binding of allosteric regulators, and 3) Identify the roles of membrane domains within the broader regulatory environment of neurons. The first aim experimentally tests a minimal model positing that single channel functions are allosterically regulated by domains within embedding membranes through tuning the availability of preferred local lipid environments. The second aim explores how the chemical potential of known allosteric regulators such as cholesterol and phosphoinositide lipids are impacted by the same thermodynamic parameters that control properties of membrane domains. The third aim investigates how membrane domains impact the sorting of enzymes that participate in protein palmitoylation and tyrosine phosphorylation regulatory pathways occurring at neuronal synapses. Experimental approaches draw on the PIs expertise using quantitative super-resolution fluorescence localization microscopy techniques and are combined with functional studies, theory, and simulation to test and refine mechanistic models of isolated and collective channel functions. The proposed work is innovative because it applies predictive models of membrane organization that are novel to both the channel and membrane domain communities. A broadly applicable framework for describing how domains modulate channel functions will drive advances in neuroscience by providing new insights into the functional basis for membrane changes with development and neurological disease, will motivate more effective and targeted treatments for neurological disease, and will connect the molecular-scale behaviors of channels to larger questions in neuroscience through the collective actions of lipids and membrane domains.

离子通道是膜结合的蛋白，通过选择性控制带电离子跨膜的流动。大多数通道都嵌入在构图中神经元膜的详细组成在调节通道功能中起着重要作用。膜可以通过特定组件与通道内的位点的结合直接调节通道结构或间接影响生物物理和生化过程以调节通道在其本地环境中起作用。对膜成分如何影响的机械理解通道功能至关重要，因为神经元膜组成的变化与正常发育和神经疾病。拟议研究的目的是测试三种不同的机制组成复杂的膜调节通道功能。工作假设， PL和COL的过去协作工作的支持是，某些渠道功能由由于这些膜是异质的，其嵌入膜的新兴特性。在广泛的初步数据的指导下，将追求三个具体目标：1）测量功能耦合通道状态到膜结构域，2）确定膜结构域如何影响变构的结合监管机构，以及3）确定膜域在更广泛的监管环境中的作用神经元。第一个目标在实验中测试了最小模型，认为单个通道功能是通过调整首选的可用性，由嵌入膜内的域进行变构调节局部脂质环境。第二个目的探讨了已知的变构调节剂的化学潜力如何例如胆固醇和磷酸肌醇脂质受到相同热力学参数的影响膜域的控制特性。第三目调查了膜域如何影响参与蛋白质棕榈酰化和酪氨酸磷酸化调节途径的酶的排序发生在神经元突触。实验方法使用定量超分辨率利用PIS专业知识荧光定位显微镜技术，并与功能研究结合，理论，以及测试和完善孤立和集体通道功能的机械模型的模拟。这拟议的工作具有创新性，因为它应用了新颖的膜组织的预测模型渠道和膜域社区。一个广泛适用的框架，用于描述如何域调节渠道功能将通过向该神经科学的发展推动神经科学的进步膜变化随发育和神经疾病的变化的功能基础，将激励更多有效和有针对性的神经疾病治疗，并将连接通过脂质和膜域的集体作用，神经科学中更大问题的渠道。