Two-pore channels (TPCs) acts as a hub for excitation-contraction coupling, metabolism and cardiac hypertrophy signalling

IF 4.3 2区 生物学 Q2 CELL BIOLOGY Cell calcium Pub Date : 2023-12-16 DOI:10.1016/j.ceca.2023.102839
Antoine de Zélicourt , Abdallah Fayssoil , Arnaud Mansart , Faouzi Zarrouki , Ahmed Karoui , Jérome Piquereau , Florence Lefebvre , Pascale Gerbaud , Delphine Mika , Mbarka Dakouane-Giudicelli , Erwan Lanchec , Miao Feng , Véronique Leblais , Régis Bobe , Jean-Marie Launay , Antony Galione , Ana Maria Gomez , Sabine de la Porte , José-Manuel Cancela
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Abstract

Ca2+ signaling is essential for cardiac contractility and excitability in heart function and remodeling. Intriguingly, little is known about the role of a new family of ion channels, the endo-lysosomal non-selective cation “two-pore channel” (TPCs) in heart function. Here we have used double TPC knock-out mice for the 1 and 2 isoforms of TPCs (Tpcn1/2−/−) and evaluated their cardiac function. Doppler-echocardiography unveils altered left ventricular (LV) systolic function associated with a LV relaxation impairment. In cardiomyocytes isolated from Tpcn1/2−/- mice, we observed a reduction in the contractile function with a decrease in the sarcoplasmic reticulum Ca2+ content and a reduced expression of various key proteins regulating Ca2+ stores, such as calsequestrin. We also found that two main regulators of the energy metabolism, AMP-activated protein kinase and mTOR, were down regulated. We found an increase in the expression of TPC1 and TPC2 in a model of transverse aortic constriction (TAC) mice and in chronically isoproterenol infused WT mice. In this last model, adaptive cardiac hypertrophy was reduced by Tpcn1/2 deletion. Here, we propose a central role for TPCs and lysosomes that could act as a hub integrating information from the excitation-contraction coupling mechanisms, cellular energy metabolism and hypertrophy signaling.

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双孔通道(TPC)是兴奋-收缩耦合、新陈代谢和心脏肥大信号的枢纽
在心脏功能和重塑过程中,Ca2+ 信号对心脏收缩力和兴奋性至关重要。耐人寻味的是,人们对一个新的离子通道家族--内溶酶体非选择性阳离子 "双孔通道"(TPCs)--在心脏功能中的作用知之甚少。在这里,我们使用了双TPC基因敲除小鼠(Tpcn1/2-/-),并对其心脏功能进行了评估。多普勒超声心动图显示,左心室收缩功能的改变与左心室松弛功能受损有关。在分离自 Tpcn1/2-/- 小鼠的心肌细胞中,我们观察到收缩功能下降,肌质网 Ca2+ 含量减少,各种调节 Ca2+ 储存的关键蛋白(如钙sequestrin)表达减少。我们还发现,能量代谢的两个主要调节因子--AMP 激活的蛋白激酶和 mTOR--也受到了下调。我们发现,在横纹主动脉缩窄(TAC)小鼠模型和长期注射异丙肾上腺素的 WT 小鼠中,TPC1 和 TPC2 的表达均有所增加。在最后一个模型中,Tpcn1/2 基因缺失会导致适应性心肌肥大减轻。在此,我们提出了 TPCs 和溶酶体的核心作用,它们可以作为一个枢纽,整合来自兴奋-收缩耦合机制、细胞能量代谢和肥大信号的信息。
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来源期刊
Cell calcium
Cell calcium 生物-细胞生物学
CiteScore
8.70
自引率
5.00%
发文量
115
审稿时长
35 days
期刊介绍: Cell Calcium covers the field of calcium metabolism and signalling in living systems, from aspects including inorganic chemistry, physiology, molecular biology and pathology. Topic themes include: Roles of calcium in regulating cellular events such as apoptosis, necrosis and organelle remodelling Influence of calcium regulation in affecting health and disease outcomes
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