TRIC-B Channels Is Critical For Physiological Functions Of Alveolar Epithelial Cells

Abstract

Trimeric intracellular cation (TRIC) channels act as counter-ion channels that function in synchronization with Ca2+ release from intracellular stores. TRIC channels have two subtypes (TRIC-A and -B) and form homo-trimers with a bullet-like structure. TRIC-B is present in most mammalian tissues, while TRIC-A is expressed in excitable tissues such as brain, heart and muscle. TRIC-A-knockout mice were viable and fertile, whereas TRIC-B-knockout mice showed neonatal lethality. Here we report on TRIC-B-knockout mice, which died within an hour after birth because of acute respiratory failure. TRIC-B-knockout mice exhibited severe cyanosis from appearance observation and respiratory acidosis from blood gas data. In light microscopy analysis, TRIC-B-knockout lung formed immature alveolar spaces and had many glycogen-rich cells. Ultrastructural analysis revealed reduction of type II alveolar epithelial cells (lamellar body positive cells), the number of lamellar body and area of lamellar body in TRIC-B-knockout type II cells. Fluorometric Ca2+ measurements showed that Ca2+ rise evoked by ATP was significantly reduced in the TRIC-B-knockout type II cells. Moreover, results from ionomycin and cyclopiazonic acid stimulation indicated Ca2+ contents in endoplasmic reticulum was significantly increase in TRIC-B-knockout type II cells.These findings indicate that TRIC-B plays an essential role in glycogenolysis, pulmonary surfactant lipid metabolism, lamellar body biogenesis, maturation of type II cells and surfactant exocytosis. In addition, it is suggested that TRIC-B supported Ca2+ release from IP3R in type II cells, because ATP-evoked Ca2+ response reduced in TRIC-B-knockout type II cells.