KCNQ CHANNELS: GATING AND SUBUNITS MODULATION

KCNQ 通道：门控和子单元调制

• 批准号: 9638596
• 负责人: JONATHAN R SILVA
• 金额: $ 33.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9638596
• 关键词: Action Potentials; Adrenergic Agents; Affect; Arrhythmia; Behavior; Brain; Chemosensitization; Coupled; Coupling; Data; Dependence; Disease; Drug Design; Epilepsy; Epithelial; Epithelium; Exercise; Exhibits; Family; Heart; Ion Channel Gating; Ion Transport; Ions; Labyrinth; Light; Long QT Syndrome; Membrane; Membrane Potentials; Modeling; Molecular; Molecular Conformation; Movement; Mutation; Neurons; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Potassium Channel; Property; Rest; Role; Signaling Molecule; Structure; Sudden Death; Symptoms; Syncope; Testing; Thyroid Gland; Work; airway epithelium; base; deafness; experience; gastrointestinal epithelium; heart function; inhibitor/antagonist; insight; malignant stomach neoplasm; novel; public health relevance; response; sensor; therapy design; tool; voltage

 DESCRIPTION (provided by applicant): This project is to reveal the major molecular bases for the function of KCNQ K+ channels (KCNQ1-5) that are important in the heart, brain, inner ear and epithelia. The aberrant functions of these channels are associated with cardiac arrhythmia, epilepsy, deafness, and gastric cancer. The importance of these channels is based on two prominent properties. First, all these channels, when expressed without auxiliary ß subunits, are activated by voltages at negative ranges (start activating around -60 mV). Being activated just above the resting membrane potential, the M-current through KCNQ2 and 3 in neurons reduces membrane excitability and acts as a "brake" to membrane discharge. Second, the association of the KCNE family K+ channel ß subunits, which radically alter gating, permeation and pharmacological properties of KCNQ1, determines the physiological role of KCNQ1. KCNQ1 associates with KCNE1 to form the IKs channel in the heart that regulates action potential duration, and with KCNE2 or KCNE3 to form the constitutively open background K+ channels in epithelia important for ion transport. What are the mechanisms underlying these properties? This is a long-standing question whose answer will provide the basis for the understanding and treatment of KCNQ associated diseases. We propose that the answer to this question lies in a novel mechanism for KCNQ1 activation. During voltage dependent activation in KCNQ1, the voltage sensor domain (VSD) moves in two steps, from the resting to intermediate and then to activated state; the channel pore opens at both intermediate and activated states of VSD, but the VSD-pore interaction differs at different states of VSD to alter channel gating, ion permeation and pharmacology. KCNE1 modulates channel function by suppressing the intermediate openings of the channel. In this project we wish to test various aspects of this hypothesis in three specific aims. 1) We wish to identify the structural motifs that are important for the VSD-pore interaction at intermediate and activated states, respectively. Mutations in KCNQ1 and KCNE1 are associated with long QT syndrome (LQT) that predispose patients to fatal cardiac arrhythmia, this study will reveal if some of the LQT mutations alter VSD-pore interaction. 2) We will examine if suppression of the intermediate and potentiation of the activated openings is the main mechanism for major functional changes upon KCNE1 association including the response to ß- adrenergic stimulation and inactivation gating. LQT patients with KCNQ1 mutations often experience symptoms of cardiac arrhythmia such as syncope and sudden death during exercise when ß-adrenergic pathway is stimulated. This study is therefore particularly significant for the understanding of molecular bases of LQT. 3) We wish to reveal if KCNE2 and 3 make the channel constitutively open by altering VSD activation, pore opening or VSD-pore interaction. We will identify if these channels are at intermediate or activated open states and their responses to drugs and cellular signaling molecules.

 描述（由适用提供）：该项目是为了揭示在心脏，大脑，内耳和上皮中很重要的KCNQ K+通道功能（KCNQ1-5）功能的主要分子碱基。这些通道的异常功能与心律不齐，癫痫，耳聋和胃癌有关。这些渠道的重要性基于两个突出的属性。首先，所有这些通道在没有辅助β亚基的情况下表达时，都会通过负范围的电压激活（开始激活-60 mV）。在静息膜电位上方激活，通过KCNQ2和3中的M电流在神经元中被激活，可减少膜的刺激，并作为膜放电的“制动”。其次，KCNE家族K+通道亚基的关联从根本上改变了KCNQ1的门控，渗透和药物特性，它决定了KCNQ1的身体作用。 KCNQ1与KCNE1相关联，以调节动作电位持续时间的心脏中形成IKS通道，并与KCNE2或KCNE3在上皮中形成组成性开放的背景K+通道对离子运输很重要。这些特性的基础机制是什么？这是一个长期以来的问题，其答案将为理解和治疗KCNQ相关疾病提供基础。我们建议这个问题的答案在于一种新型的KCNQ1激活机制。在KCNQ1中的电压依赖激活过程中，电压传感器结构域（VSD）分为两个步骤，从静止状态到中间，然后是激活状态。通道孔在VSD的中间和激活状态下都打开，但是VSD不同状态的VSD孔相互作用差异以改变通道门控，离子渗透和药理学。 KCNE1通过抑制通道的中间开口来调节通道函数。在这个项目中，我们希望以三个具体目标来检验该假设的各个方面。 1）我们希望确定分别对中间和激活状态下VSD孔相互作用很重要的结构基序。 KCNQ1和KCNE1中的突变与长长的QT综合征（LQT）有关，使患者容易患有致命的心律不齐，这项研究将揭示是否某些LQT突变是否改变了VSD孔隙2），我们将检查抑制激活孔的中间体和电位的抑制，包括kccenigation的抑制 - kccne的主要机制是kccne1的主要机制。门控。当刺激β-肾上腺素途径时，患有KCNQ1突变的LQT患者经常会出现心律不齐的症状，例如晕厥和突然死亡。因此，这项研究对于理解LQT的分子碱基特别重要。 3）我们希望揭示KCNE2和3是否通过改变VSD激活，孔隙打开或VSD孔相互作用来始终如一地打开通道。我们将确定这些通道是否处于中间或激活的开放状态及其对药物和细胞信号分子的反应。

项目成果

Arrhythmia-associated calmodulin variants interact with KCNQ1 to confer aberrant membrane trafficking and function.

• DOI: 10.1093/pnasnexus/pgad335
• 发表时间: 2023-11
• 期刊: PNAS NEXUS
• 作者: Kang, Po wei;Woodbury, Lucy;Angsutararux, Paweorn;Sambare, Namit;Shi, Jingyi;Marras, Martina;Abella, Carlota;Bedi, Anish;Zinn, DeShawn;Cui, Jianmin;Silva, Jonathan R.
• 通讯作者: Silva, Jonathan R.