Multiple Activity Patterns of Acetylcholine Receptors

乙酰胆碱受体的多种活性模式

• 批准号: 8806724
• 负责人: Anthony L Auerbach
• 金额: $ 53.05万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8806724
• 关键词: Address; Adult; Affinity; Agonist; Amino Acids; Binding; Binding Sites; Biological Models; Cells; Chemicals; Cholinergic Receptors; Communication; Complementary DNA; Coupling; DNA Sequence Rearrangement; Diffusion; Disease; Distant; Dose; Elements; Entropy; Equilibrium; Event; Extracellular Domain; Foundations; Free Energy; Gases; Goals; Health; Ion Channel; Ions; Kinetics; Knowledge; Learning; Ligand Binding; Ligands; Link; Measurement; Measures; Mechanics; Membrane; Microscopic; Molecular; Movement; Mus; Muscle; Mutation; Nerve; Neurosciences; Neurotransmitter Receptor; Neurotransmitters; Nicotinic Receptors; Pattern; Pharmacology; Physiology; Probability; Process; Property; Proteins; Reaction; Relative (related person); Resolution; Rest; Side; Signal Transduction; Site; Structure; Sum; Synapses; Synaptic Receptors; Synaptic Transmission; Temperature; Testing; Theophylline; Thermodynamics; Time; Transmembrane Domain; Vertebral column; chemical reaction; instrument; network models; neuromuscular; receptor; research study; response; sensor; single molecule; tool

DESCRIPTION (provided by applicant): Signaling at the neuromuscular synapse requires C(losed-channel)O(pen-channel) 'gating' of acetylcholine receptors (AChRs). The thermodynamic foundation of this allosteric transition is well understood: transmitter molecules released from the nerve terminal bind to AChRs with higher affinity to O vs. C to increase the probability that the channel is Open. The microscopic events within CO are less certain. We will use single-channel kinetics and phi-value analysis to probe the interior of AChR gating and illuminate the ultra-fast protein rearrangements within this reaction. So far, results show that AChRs change from C-to-O in 4 steps. The first amino acids to move are not at the transmitter binding sites but in a distant membrane domain linker that joins the M2 and M3 helices of the subunit. Further, the unlocking of a double-gate in M2 (all subunits) occurs in the final 2 gating activation steps. Most side chain gating movements are 'resettling' events that have only local energetic consequences. We will investigate two new hypotheses for AChR gating: 1) communication between the binding sites and the gate is not by a structural-mechanical process but, rather, by the vibrational entropy of the entire backbone, and 2) allosteric communication commences with low-affinity binding of the agonist to the resting receptor.

描述（由申请人提供）：神经肌肉突触的信号传导需要C（封闭通道）乙酰胆碱受体（AChR）的O（笔通道）“门控”。这种变构转变的热力学基础已得到充分理解：从神经末梢释放的递质分子以与O比C更高的亲和力与AChR结合，以增加通道开放的可能性。C中的微观事件O不太确定。我们将使用单通道动力学和φ值分析来探测AChR门控的内部，并阐明该反应中的超快蛋白质重排。到目前为止，研究结果表明，AChRs从C到O的变化分为4个步骤。第一个移动的氨基酸不是在递质结合位点，而是在连接亚基的M2和M3螺旋的远端膜结构域接头中。此外，M2（所有子单元）中的双门的解锁发生在最后2个门控激活步骤中。大多数侧链门控运动是“重置”事件，只具有局部能量后果。我们将研究两个新的假设AChR门：1）结合位点和门之间的通信不是通过结构力学过程，而是通过整个骨架的振动熵，和2）变构通信开始与低亲和力结合的激动剂静息受体。