катехоламинергический多态室内心动脉冲动相关的氨酸受体变体表现出域特异性泄漏和calmodulin亲属性属性
Hitoshi Uchinoumi1,2, Xiaoqiong Dong1, Ivanita Stefanon1,3
1Department of Pharmacology, University of California, Davis, California, USA.
The Journal of physiology
|May 5, 2025
概括
在RyR2通道中,catecholaminergic多态心室性心力衰竭 (CPVT) 变体在基线时没有显示出病理三部曲. 然而,蛋白质激酶A的激活会在N端和中心变体中诱导这种三元组,但不是孔域变体.
科学领域:
- 心血管研究研究心血管研究
- 分子心脏病学分子心脏病学
- 遗传学 是一个遗传学.
背景情况:
- catecholaminergic多形心室性心跳动 (CPVT) 是一种与心脏瑞诺丁受体2 (RyR2) 变异相关的遗传性心律失常.
- RyR2变体可能会导致 (Ca2+) 从肉质细胞网膜 (SR) 泄漏的增加,导致压力诱导的心律失常.
- 一个先前确定的病理性RyR2构造涉及减少calmodulin结合,增加DPc10结合,并增强了对dantrolene敏感的扩张性Ca2+泄漏.
研究的目的:
- 调查 CPVT 相关的 RyR2 变体在 N-终端,中心和 C-终端域是否表现出这种病态的 RyR2 构造 (三部曲) 在敲入小鼠模型中.
- 为了确定病理三重曲线是否存在于基线或由这些CPVT变体中的特定信号通路诱导.
- 在不同的CPVT变异域中区分 RyR2 功能障碍背后的分子机制.
主要方法:
- 使用了来自CPVT敲门 (KI) 鼠标的管肌细胞,其中包含N端 (R176Q/+),中央 (R2474S/+) 和C端 (R4496C/+) RyR2变异.
- 与野生型 (WT) 肌细胞相比,在KI肌细胞中评估了calmodulin (CaM) 和解压 (DPc10) 与RyR2的基线结合亲缘关系.
- 使用循环腺单酸盐 (cAMP) 刺激 RyR2 酸化以模仿蛋白激酶A (PKA) 激活,并评估了 CaM/DPc10 结合和 SR Ca2+ 泄漏的后续变化.
主要成果:
- 在基线时,所有三种KI小鼠模型 (R176Q,R2474S,R4496C) 的心室肌细胞与WT肌细胞相比,在CaM和DPc10与RyR2结合方面没有差异.
- 在cAMP刺激后,病理三组 (减少CaM亲和力,增强DPc10结合,增加Ca2+泄漏) 仅在N端 (R176Q/+) 和中心 (R2474S/+) RyR2变异KI肌细胞中观察到.
- 相比之下,cAMP在C端/孔域 (R4496C/+) KI肌细胞和WT肌细胞中的刺激增加了SR Ca2+泄漏,但没有改变CaM或DPc10结合亲和力.
结论:
- 与N终端和中心域中的CPVT相关的RyR2变异,与C终端/毛孔域变异不同,在PKA激活时会发展出一种病态的透气式RyR2构造.
- 在不同RyR2领域的CPVT变体中,心律失常的RyR2 Ca2+泄漏的机制不同.
- 这些发现表明,针对病理三重构形状的治疗策略可能是CPVT患者的变异特异.
相关概念视频
Antihypertensive Drugs: Action of Calcium Channel Blockers
393
Calcium ions are essential to contract smooth muscle cells in blood vessels. They enter these cells through voltage-dependent calcium channels, specifically L-type calcium channels in the cell membrane. These L-type calcium channels are integral to the excitation-contraction coupling process in smooth muscle. When a stimulus is received by smooth muscle cells, their membrane depolarizes. This alteration in membrane potential instigates the opening of L-type calcium channels. As a result,...
393
Antianginal Drugs: Calcium Channel Blockers and Ranolazine
385
Angina pectoris, a primary symptom of ischemic heart disease, requires careful pharmacological interventions. In this context, calcium channel blockers (CCBs) and ranolazine have emerged as crucial pharmacotherapeutic agents, providing deep insights into the complexities of angina management.
CCBs, a diverse class that includes dihydropyridines (nifedipine) and diphenylalkylamines (verapamil and diltiazem), exert their effect by blocking calcium channels in cardiac and smooth muscle cells. This...
CCBs, a diverse class that includes dihydropyridines (nifedipine) and diphenylalkylamines (verapamil and diltiazem), exert their effect by blocking calcium channels in cardiac and smooth muscle cells. This...
385
Calmodulin-dependent Signaling
4.8K
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
4.8K
Antiarrhythmic Drugs: Class IV Agents as Calcium Channel Blockers
674
Class IV antiarrhythmic drugs, such as verapamil and diltiazem, block calcium channels. They primarily affect the heart, slowing the conduction in calcium-dependent tissues like the SA and AV nodes. These drugs manage reentrant supraventricular tachycardia (SVT) and reduce ventricular rate in atrial flutter/fibrillation.
Verapamil, a calcium channel blocker, inhibits calcium movement across myocardial cell membranes and vascular smooth muscle. This results in the dilation of coronary and...
Verapamil, a calcium channel blocker, inhibits calcium movement across myocardial cell membranes and vascular smooth muscle. This results in the dilation of coronary and...
674
Mechanism of Cardiac Arrhythmias
849
Arrhythmias are irregular heart rhythms occurring when the heart's electrical impulses become abnormal. These disturbances can lead to various symptoms, depending on their severity and the underlying cause. Some common factors contributing to arrhythmias include hypoxia, ischemia, electrolyte imbalances, excessive catecholamine exposure, drug toxicity, and muscle overstretching. Arrhythmias can be classified into two main types based on the rate and site of origin of abnormal heart rhythms.
849
Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers
640
Adrenergic stimulation generally impacts cardiac rate and rhythm. Specifically, stimulation of the β-adrenoceptors triggers an increase in intracellular calcium ion influx and pacemaker currents, which may cause arrhythmias. Catecholamines like adrenaline also demonstrate β2-adrenoceptor-mediated hypokalemia, impacting cardiac action potential and disrupting the normal cardiac rhythm. Class II antiarrhythmic drugs are β-adrenoceptor antagonists or β-blockers, which...
640


