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Activation of the death receptor Fas has been reported to produce a two-phase intracellular Ca(2+) release response in coronary arterial myocytes (CAMs), which consists of local Ca(2+) bursts via lysosomal transient potential receptor-mucolipin 1 (TRP-ML1) channels and consequent Ca(2+) release from the sarcoplasmic reticulum (SR). The present study was designed to explore the molecular mechanism by which lysosomal Ca(2+) bursts are coupled with SR Ca(2+) release in mouse CAMs and to determine the functional relevance of this lysosome-associated two-phase Ca(2+) release to apoptosis, a common action of Fas activation with Fas ligand (FasL). By confocal microscopy, we found that transfection of CAMs with TRP-ML1 small interfering (si)RNA substantially inhibited FasL (10 ng/ml)-induced lysosome Ca(2+) bursts and consequent SR Ca(2+) release. In contrast, transfection of CAMs with plasmids containing a full-length TRP-ML1 gene enhanced FasL-induced two-phase Ca(2+) release. We further demonstrated that FasL significantly increased the colocalization of the lysosomal marker Lamp1 with ryanodine receptor 3 and enhanced a dynamic trafficking of lysosomes to the SR. When CAMs were treated with TRP-ML1 siRNA, FasL-induced interactions between the lysosomes and SR were substantially blocked. Functionally, FasL-induced apoptosis and activation of calpain and calcineurin, the Ca(2+) sensitive proteins that mediate apoptosis, were significantly attenuated by silencing TRP-ML1 gene but enhanced by overexpression of TRP-ML1 gene. These results suggest that TRP-ML1 channel-mediated lysosomal Ca(2+) bursts upon FasL stimulation promote lysosome trafficking and interactions with the SR, leading to apoptosis of CAMs via a Ca(2+)-dependent mechanism.


Ming Xu, Xiaoxue Li, Scott W Walsh, Yang Zhang, Justine M Abais, Krishna M Boini, Pin-Lan Li. Intracellular two-phase Ca2+ release and apoptosis controlled by TRP-ML1 channel activity in coronary arterial myocytes. American journal of physiology. Cell physiology. 2013 Mar 1;304(5):C458-66

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PMID: 23283937

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