Allostery and voltage sensing of membrane proteins

膜蛋白的变构和电压传感

• 批准号: 8457601
• 负责人: Michael Priest
• 金额: $ 4.22万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2015-09-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457601
• 关键词: 4-Aminopyridine; Affinity; Binding Sites; Brain; Cells; Drug Delivery Systems; Engineering; Frequencies; G-Protein-Coupled Receptors; Gated Ion Channel; Goals; Health; Heart; Human; Lead; Length; Ligand Binding; Ligands; Location; Measures; Membrane Potentials; Membrane Proteins; Movement; Multiple Sclerosis; Muscarinic Acetylcholine Receptor; Names; Oocytes; Play; Potassium; Potassium Channel; Property; Proteins; Role; Signal Transduction; System; Techniques; Testing; Therapeutic; Transmembrane Domain; Voltage-Clamp Technics; Voltage-Gated Potassium Channel; Xenopus oocyte; extracellular; improved; monomer; novel; protein phosphatase inhibitor-2; response; sensor; therapeutic target; voltage

DESCRIPTION (provided by applicant): This project has the goal of understanding the allosteric modulation, through voltage sensing, of voltage-gated ion channels and GPCRs has on their function. Allosteric modulation of voltage-gated ion channels occurs via domains not directly needed for voltage sensing and gating, that is, the first three transmembrane domains of each monomer, and the linker attaching this domain to the remainder of the protein. Allosteric modulation of GPCR activity occurs through voltage-sensing. Engineered versions of the Shaker potassium channel and the muscarinic acetylcholine receptor type 2 will be expressed in Xenopus oocytes and probed using electrophysiological and fluorescent techniques. The aims are to understand the role the linker between the third and fourth transmembrane domains of voltage-gated potassium channels plays in its function, to understand the movements that occur in the second and third transmembrane domains upon changes in membrane potential, independent of the movement of the primary voltage sensor in the fourth transmembrane domain, and to understand the movements that occur in response to changes in membrane potential in GPCRs. The long-term objectives of this project are to advance our understanding of potential novel targets for therapeutics targeted to modulate the voltage-sensing properties of voltage-gated ion channels and GPCRs. As these membrane proteins are already successful targets for many therapies, improved understanding of how to modulate their function should lead towards improvements of human health. PUBLIC HEALTH RELEVANCE: Voltage-gated ion channels and GPCRs are voltage-sensitive membrane proteins; their proper functioning is crucial for appropriate signaling between cells, for the activity of the brain, and for the beating of the heart. Understanding the movements these membrane proteins make in response to electrical changes, and which parts of the proteins are necessary for the protein to function correctly, will greatly improve the ability to produce novel therapies and drugs that target these proteins.

描述（由申请人提供）：该项目的目的是通过电压门控离子通道和GPCR在其功能上了解变构调制，通过电压传感。电压门控离子通道的变构调节是通过不直接需要的电压传感和门控进行的，即每个单体的前三​​个跨膜结构域，以及将该域连接到其余蛋白质的接头。 GPCR活性的变构调节是通过电压传感发生的。振动钾通道的工程版本和毒蕈碱乙酰胆碱受体2型将以武虫卵母细胞表达，并使用电生理和荧光技术进行探测。其目的是了解电压门控钾通道的第三和第四跨膜结构域之间的连接器在其功能中发挥作用，以了解膜电位变化的第二和第三跨膜域中发生的运动，而与第四跨跨跨跨跨跨跨跨跨跨跨跨跨跨跨跨跨跨跨跨跨跨度传感器的运动无关。该项目的长期目标是促进我们对针对调节电压门控离子通道和GPCR的电压感应特性的潜在新型治疗剂的理解。由于这些膜蛋白已经是许多疗法的成功靶标，因此对如何调节其功能的理解得到了改善，应导致改善人类健康。 公共卫生相关性：电压门控离子通道和GPCR是对电压敏感的膜蛋白；它们的适当功能对于细胞之间的适当信号，大脑的活性以及心脏跳动至关重要。了解这些膜蛋白会响应电动变化而产生的运动，以及蛋白质的哪些部分才能正确起作用，将大大提高产生针对这些蛋白质的新型疗法和药物的能力。