Allosteric Modulation of HCN Channels

HCN 通道的变构调制

• 批准号: 10367342
• 负责人: CATHERINE PROENZA
• 金额: $ 43.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367342
• 关键词: Biophysical Process; Bladder; Cells; Colon; Cyclic AMP; Cyclic Nucleotides; Cytoplasmic Tail; Data; Dependence; Development; Epilepsy; FDA approved; Goals; HCN4 gene; Heart failure; Integral Membrane Protein; Interstitial Cell of Cajal; MRVI1 gene; Membrane Potentials; Mental Depression; Molecular; Neurogenic Bladder; Neurons; Peripheral; Pharmaceutical Preparations; Physiological; Protein Isoforms; Proteins; Regulation; Role; Sensory; Site; Specificity; cell type; gain of function; gastrointestinal; improved; inhibitor/antagonist; ivabradine; loss of function; motility disorder; new therapeutic target; nodal myocyte; novel; novel therapeutics; painful neuropathy; targeted treatment; voltage

PROJECT SUMMARY Hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels are critical determinants of membrane potential and excitability in many types of cells throughout the body, including cardiac pacemaker cells, central and peripheral neurons, many types of sensory cells, and interstitial cells of Cajal in the colon and bladder. Consistent with this widespread distribution, HCN channels have been identified as potential drug targets for treatment of a long list of conditions including angina, heart failure, epilepsy, neuropathic pain, depression, gastrointestinal dysmotility, and neurogenic bladder. However, the single FDA-approved HCN channel drug (ivabradine) is limited, owing in part to its non-selective block of all four mammalian HCN channels isoforms and its off-target block of Kv11.1 (hERG), Nav1.5, and Cav1.2 channels. The need for new, isoform-specific HCN channel activators and inhibitors has been widely recognized but the lack of information about allosteric and isoform-specific regulation of HCN channels is a roadblock to the development of novel therapeutics. The long-term goals of this project are to identify naturally-occurring, allosteric regulators of HCN channels and to understand their mechanisms of action. Achieving these goals will advance understanding of the physiological and molecular functions of HCN channels and aid in the development of new HCN channel drugs. The current proposal focuses on our exciting discovery of LRMP and IRAG as two novel, isoform- specific protein interaction partners of HCN4 channels. LRMP and IRAG are homologous ER transmembrane proteins that have large cytoplasmic domains. Importantly, LRMP and IRAG only modulate the HCN4 isoform. Moreover, the two proteins have opposing effects on HCN4: LRMP causes a loss-of-function (LOF) by decreasing the canonical depolarizing shift in voltage-dependence induced by cAMP while IRAG causes gain- of-function (GOF) by shifting the basal voltage dependence of HCN4 to more positive potentials. Preliminary data establish that IRAG is co-expressed with HCN4 in cardiac pacemaker cells. Proposed aims will identify interaction sites on the three proteins, determine the molecular mechanisms for the distinct and isoform- specific effects, and evaluate their role in pacemaker cells.

项目摘要 超极化激活，环状核苷酸敏感（HCN）通道是关键决定因素 整个体内许多类型细胞的膜电位和兴奋性，包括心脏起搏器 细胞，中央和周围神经元，许多类型的感觉细胞以及结肠中Cajal的间质细胞 膀胱。与这种广泛的分布一致，HCN通道已被确定为潜在药物 治疗一系列疾病的目标，包括心绞痛，心力衰竭，癫痫，神经性疼痛， 抑郁症，胃肠道功能障碍和神经源性膀胱。但是，单个FDA批准的HCN 通道药物（ivabradine）受到限制，部分原因是其所有四个哺乳动物HCN的非选择性块 通道同工型及其脱靶块的KV11.1（HERG），NAV1.5和CAV1.2频道。需要新的 同工型特异性的HCN通道激活剂和抑制剂已被广泛认可，但缺乏信息 关于HCN通道的变构和同工型特异性调节是新型发展的障碍 疗法。 该项目的长期目标是确定HCN渠道的自然存在的变构调节器 并了解他们的行动机制。实现这些目标将提高对 HCN通道的生理和分子功能，并有助于开发新的HCN通道 毒品。当前的提案着重于我们对LRMP和IRAG的激动人心的发现，这是两种小说，同工型 - HCN4通道的特定蛋白质相互作用伙伴。 LRMP和IRAG是同源的ER跨膜 具有较大细胞质结构域的蛋白质。重要的是，LRMP和IRAG仅调节HCN4同工型。 此外，这两种蛋白质对HCN4具有相反的影响：LRMP导致功能丧失（LOF）。 减少cAMP诱导的电压依赖性的规范去极化转移，而IRAG会导致增益 功能（GOF）通过将HCN4的基础电压依赖性转移到更积极的电位上。初步的 数据表明，IRAG与心脏起搏器细胞中的HCN4共表达。拟议的目标将确定 三种蛋白质上的相互作用位点，确定不同和同工型的分子机制 特定效果，并评估其在起搏器细胞中的作用。