The Role of Ca2+ Handling in TRIC Knockout Neonatal Cardiomyocytes

Abstract

Trimeric intracellular cation (TRIC) channel subtypes, namely TRIC-A and TRIC-B, are essential counter-ion permeability pathway associated with rapid Ca2+ release from intracellular stores. TRIC-A abundantly expressed in excitable tissues including brain, heart, smooth muscle and skeletal muscle, whereas TRIC-B is ubiquitously expressed throughout tissues. Though TRIC-A-knockout mice are normal in terms of growth, the mice developed hypertension even at young-adult stage. On the other hand, TRIC-B-knockout mice exhibit neonatal lethality due to respiratory failure. Moreover, knockout mice lacking both TRIC channel subtypes exhibit embryonic heart failure, and the mutant cardiomyocytes show compromised ryanodine receptor (RyR)-mediated Ca2+ release. These evidences are indicating that TRIC channel subtypes possess compatible functions in embryonic cardiomyocytes.Because of neonatal lethality occurs in TRIC-B-knockout mice, we examined Ca2+ handling properties in wild-type, TRIC-A-knockout and TRIC-B-knockout neonatal cardiomyocytes. Resting Ca2+ level and Ca2+ transient frequency under isoproterenol treatment were enhanced in TRIC-B-kncokout cardiomyocytes, and caffeine responses under Ca2+-free condition was amplified in both knockout cardiomyocytes.Therefore, TRIC channels are likely to act coordinately on synchronization with Ca2+ release from sarcoplasmic reticulum to maintain normal cardiac function. Furthermore, TRIC-A-knockout mice showed arrhythmia under acutely isoproterenol injection and reduction of Ca2+ spark frequency. Resting Ca2+ level and Ca2+ transient amplitude were augmented in adult TRIC-A-knockout cardiomyocytes. These results seem to support this study.