| First Author | de Zélicourt A | Year | 2024 |
| Journal | Cell Calcium | Volume | 117 |
| Pages | 102839 | PubMed ID | 38134531 |
| Mgi Jnum | J:358631 | Mgi Id | MGI:7782694 |
| Doi | 10.1016/j.ceca.2023.102839 | Citation | de Zelicourt A, et al. (2024) Two-pore channels (TPCs) acts as a hub for excitation-contraction coupling, metabolism and cardiac hypertrophy signalling. Cell Calcium 117:102839 |
| abstractText | Ca(2+) 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 Ca(2+) content and a reduced expression of various key proteins regulating Ca(2+) 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. |
