Intracellular two-phase Ca2+ release and apoptosis controlled by TRP-ML1 channel activity in coronary arterial myocytes

Ming Xu, Xiaoxue Li, Scott W. Walsh, Yang Zhang, Justine M. Abais, Krishna M. Boini, Pin Lan Li

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Activation of the death receptor Fas has been reported to produce a two-phase intracellular Ca2+ release response in coronary arterial myocytes (CAMs), which consists of local Ca2+ bursts via lysosomal transient potential receptor-mucolipin 1 (TRP-ML1) channels and consequent Ca2+ release from the sarcoplasmic reticulum (SR). The present study was designed to explore the molecular mechanism by which lysosomal Ca2+ bursts are coupled with SR Ca2+ release in mouse CAMs and to determine the functional relevance of this lysosome-associated two-phase Ca2+ 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 Ca2+ bursts and consequent SR Ca2+ release. In contrast, transfection of CAMs with plasmids containing a full-length TRP-ML1 gene enhanced FasL-induced two-phase Ca2+ 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 Ca2+ 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 Ca2+ bursts upon FasL stimulation promote lysosome trafficking and interactions with the SR, leading to apoptosis of CAMs via a Ca2+-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)C458-C466
JournalAmerican Journal of Physiology - Cell Physiology
Volume304
Issue number5
DOIs
StatePublished - Mar 11 2013
Externally publishedYes

Keywords

  • Ca mobilization
  • Programmed cell death
  • Signaling lysosomes
  • Transient receptor potential channel

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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