Ca 2+-permeable channels in the hepatocyte plasma membrane and their roles in hepatocyte physiology

Abstract

Hepatocytes are highly differentiated and spatially polarised cells which conduct a wide range of functions, including intermediary metabolism, protein synthesis and secretion, and the synthesis, transport and secretion of bile acids. Changes in the concentrations of Ca 2+ in the cytoplasmic space, endoplasmic reticulum (ER), mitochondria, and other intracellular organelles make an essential contribution to the regulation of these hepatocyte functions. While not yet fully understood, the spatial and temporal parameters of the cytoplasmic Ca 2+ signals and the entry of Ca 2+ through Ca 2+-permeable channels in the plasma membrane are critical to the regulation by Ca 2+ of hepatocyte function. Ca 2+ entry across the hepatocyte plasma membrane has been studied in hepatocytes in situ, in isolated hepatocytes and in liver cell lines. The types of Ca 2+-permeable channels identified are store-operated, ligand-gated, receptor-activated and stretch-activated channels, and these may vary depending on the animal species studied. Rat liver cell store-operated Ca 2+ channels (SOCs) have a high selectivity for Ca 2+ and characteristics similar to those of the Ca 2+ release activated Ca 2+ channels in lymphocytes and mast cells. Liver cell SOCs are activated by a decrease in Ca 2+ in a sub-region of the ER enriched in type1 IP 3 receptors. Activation requires stromal interaction molecule type 1 (STIM1), and G i2α, F-actin and PLCγ1 as facilitatory proteins. P 2x purinergic channels are the only ligand-gated Ca 2+-permeable channels in the liver cell membrane identified so far. Several types of receptor-activated Ca 2+ channels have been identified, and some partially characterised. It is likely that TRP (transient receptor potential) polypeptides, which can form Ca 2+- and Na +-permeable channels, comprise many hepatocyte receptor-activated Ca 2+-permeable channels. A number of TRP proteins have been detected in hepatocytes and in liver cell lines. Further experiments are required to characterise the receptor-activated Ca 2+ permeable channels more fully, and to determine the molecular nature, mechanisms of activation, and precise physiological functions of each of the different hepatocyte plasma membrane Ca 2+ permeable channels.