Regulation of cardiac ion channel function via allosteric modulators

通过变构调节剂调节心脏离子通道功能

基本信息

项目摘要

DESCRIPTION (provided by applicant): The ryanodine receptor (RyR) is comprised of 4 RyR protomers and proteins that bind to the cytoplasmic domain of the channel forming a macromolecular signaling complex. This proposal addresses the mechanisms by which allosteric modulators regulate RyR function. Two specific forms of allosteric modulation will be examined: 1) regulation of the channel by derivatives of 1,4-benzothiazepines that potently effect channel gating via allosteric effects; 2) regulation of the channel by protein-protein interactions with the stabilizing subunit FKBP12/12.6 (calstabin1/2). Four aims are proposed: Aim 1: Allosteric regulation of RyR2 by small molecules that enhance binding of calstabin2 to RyR2. Effects of 1,4- benzothiazepine derivatives on RyR2 channel function will be examined using RyR2 channels reconstituted into planar lipid bilayers. The binding site on RyR2 for the 1,4-benzothiazepine derivatives will be identified using photoaffinity radiolabels. The hypothesis is derivatives of 1,4-benzothiazepines bind to and allosterically modulate the function of RyR2 and RyR1. Aim 2: Allosteric modulation of RyR2 as a mechanism for preventing cardiac arrhythmias RyR2 are PKA hyperphosphorylated and "leaky" in atrial fibrillation (AF) and JTV519 prevents exercised induced cardiac arrhythmias in WT and calstabin2+/- mice but not in calstabin2-/- mice indicating that the mechanism of action of this novel anti-arrhythmic drug requires calstabin2. The hypothesis is small molecules that enhance calstabin2 binding to RyR2 can prevent cardiac arrhythmias via allosteric modulation of RyR2. Using genetic mouse models harboring RyR2 mutations linked to sudden cardiac death in humans, and RyR2 mutations that mimic constitutively PKA phosphorylated or non-phosphorylatable RyR2 and animal models of AF, and myocardial infarction, we will determine whether enhancing binding of calstabin2 to RyR2 prevents cardiac arrhythmias. Aim 3: Stabilization of calstabin2 binding to RyR2 as a mechanism for treating heart failure (HF). RyR2 are PKA hyperphosphorylated and depleted of calstabin2 in HF and JTV519 improves cardiac function in WT and calstabin2+/- mice but not in calstabin2-/- mice. Using genetic mouse models and models of myocardial infarction, we will determine whether enhancing binding of calstabin2 to RyR2 using JTV519 that modify RyR2 via allosteric effects improve cardiac function in HF. Skeletal muscle fatigue is increased and RyR1 are PKA hyperphosphorylated and depleted of calstabin1 in HF, and JTV519 induces rebinding of calstabin1 to RyR1 probably via an allosteric effect on the channel. Using animal models of myocardial infarction and HF, we will investigate whether JTV519 improves skeletal muscle function in HF. The studies are significant because they may lead to a novel therapeutic approach based on allosteric modulation of RyR that can result in improved therapy for human cardiovascular diseases.
描述(由申请人提供):ryanodine受体(RYR)由4个RYR原始物和蛋白质组成,它们与形成大分子分子信号传导复合物的通道的细胞质结构域结合。该提案解决了变构调节器调节RYR功能的机制。将检查两种特定形式的变构调节:1)通过1,4-苯锡辛的衍生物调节通道,通过变构效应强烈影响通道门控; 2)通过蛋白质蛋白质与稳定亚基FKBP12/12.6(Calstabin1/2)相互作用来调节通道。提出了四个目标:目标1:小分子对RyR2的变构调节,从而增强calstabin2与RyR2的结合。 1,4-苯锡锡氮卓类衍生物对RYR2通道功能的影响将使用RYR2通道重构为平面脂质双层。 RYR2上的结合位点将使用光性放射性标记鉴定为1,4-苯甲噻嗪衍生物。该假设是1,4-苯甲噻嗪的衍生物与RYR2和RYR1的功能结合并变构调节。 AIM 2:对RYR2作为预防心律不齐的RYR2的机制变构调节是PKA高磷酸化和心房颤动中的“漏水”(AF)和JTV519可预防WT和Calstabin2 +/-小鼠的诱导性心律失常的诱导心律失常,但在Calstabin2 +/-小鼠中进行了指示 - 抗心律失常需要Calstabin2。假设是小分子,可以增强与RyR2结合的Calstabin2结合可以通过RYR2的变构调节来预防心律不齐。使用具有与人类猝死有关的RYR2突变的遗传小鼠模型,以及模仿PKA PKA磷酸化或非磷酸化的RYR2的RYR2突变以及AF的动物模型以及心肌梗死的动物模型,我们将确定加强calstabin2对Ryr2预期Cardiac Cardias Cardmias的结合。 AIM 3:稳定Calstabin2与RYR2结合,作为治疗心力衰竭(HF)的机制。 RyR2是PKA高磷酸化并耗尽了HF中的Calstabin2,JTV519改善了WT和Calstabin2 +/-小鼠的心脏功能,但在Calstabin2 - / - 小鼠中不改善心脏功能。使用遗传小鼠模型和心肌梗死模型,我们将使用JTV519确定calstabin2与RyR2的结合是否通过变构效应改善RYR2可以改善HF中的心脏功能。骨骼肌疲劳增加,RyR1被PKA高磷酸化并耗尽了Calstabin1,而JTV519可能会通过对通道的变构效应来诱导Calstabin1重新固定为RyR1。使用心肌梗塞和HF的动物模型,我们将研究JTV519是否可以改善HF中的骨骼肌功能。这些研究之所以重要,是因为它们可能会基于RYR的变构调节而导致一种新型的治疗方法,从而可以改善对人类心血管疾病的治疗。

项目成果

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ANDREW Robert MARKS其他文献

ANDREW Robert MARKS的其他文献

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{{ truncateString('ANDREW Robert MARKS', 18)}}的其他基金

Ryanodine receptor structure and function in heart failure
Ryanodine 受体结构和心力衰竭中的功能
  • 批准号:
    10628917
  • 财政年份:
    2023
  • 资助金额:
    $ 40.25万
  • 项目类别:
Summer Program for Under Represented Students (SPURS)
弱势学生暑期项目 (SPURS)
  • 批准号:
    10583050
  • 财政年份:
    2022
  • 资助金额:
    $ 40.25万
  • 项目类别:
Training in Cardiovascular Sciences for Under Represented Students
为代表性不足的学生提供心血管科学培训
  • 批准号:
    10669557
  • 财政年份:
    2021
  • 资助金额:
    $ 40.25万
  • 项目类别:
Training in Cardiovascular Sciences for Under Represented Students
为代表性不足的学生提供心血管科学培训
  • 批准号:
    10115469
  • 财政年份:
    2021
  • 资助金额:
    $ 40.25万
  • 项目类别:
Training in Cardiovascular Sciences for Under Represented Students
为代表性不足的学生提供心血管科学培训
  • 批准号:
    10397516
  • 财政年份:
    2021
  • 资助金额:
    $ 40.25万
  • 项目类别:
Calcium and the Pathophysiology of Neurodegenerative Disorders
钙与神经退行性疾病的病理生理学
  • 批准号:
    10052965
  • 财政年份:
    2020
  • 资助金额:
    $ 40.25万
  • 项目类别:
Calcium and the physiology of diabetes
钙与糖尿病的生理学
  • 批准号:
    10357858
  • 财政年份:
    2019
  • 资助金额:
    $ 40.25万
  • 项目类别:
Structure-function analysis for elucidating pathogenicity of cardiac ryanodine receptor genetic variants
结构功能分析阐明心脏兰尼碱受体遗传变异的致病性
  • 批准号:
    10407960
  • 财政年份:
    2019
  • 资助金额:
    $ 40.25万
  • 项目类别:
Ryanodine Receptor Defects in Cardiomyopathy Caused by Lamin A/C Gene Mutations
Lamin A/C 基因突变引起的心肌病中的 Ryanodine 受体缺陷
  • 批准号:
    9904328
  • 财政年份:
    2019
  • 资助金额:
    $ 40.25万
  • 项目类别:
Calcium and the physiology of diabetes
钙与糖尿病的生理学
  • 批准号:
    9923637
  • 财政年份:
    2019
  • 资助金额:
    $ 40.25万
  • 项目类别:

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Na-Ca2 交换的钠依赖性失活:与心脏功能的相关性
  • 批准号:
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Dynamic Calmodulin Regulation of Na Channels
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