Ca2+-permeable channels in the hepatocyte plasma membrane and their roles in hepatocyte physiology

AbstractHepatocytes 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 Ca2+ 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 Ca2+ signals and the entry of Ca2+ through Ca2+-permeable channels in the plasma membrane are critical to the regulation by Ca2+ of hepatocyte function. Ca2+ entry across the hepatocyte plasma membrane has been studied in hepatocytes in situ, in isolated hepatocytes and in liver cell lines. The types of Ca2+-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 Ca2+ channels (SOCs) have a high selectivity for Ca2+ and characteristics similar to those of the Ca2+ release activated Ca2+ channels in lymphocytes and mast cells. Liver cell SOCs are activated by a decrease in Ca2+ in a sub-region of the ER enriched in type1 IP3 receptors. Activation requires stromal interaction molecule type 1 (STIM1), and Gi2α, F-actin and PLCγ1 as facilitatory proteins. P2x purinergic channels are the only ligand-gated Ca2+-permeable channels in the liver cell membrane identified so far. Several types of receptor-activated Ca2+ channels have been identified, and some partially characterised. It is likely that TRP (transient receptor potential) polypeptides, which can form Ca2+- and Na+-permeable channels, comprise many hepatocyte receptor-activated Ca2+-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 Ca2+ 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 Ca2+ permeable channels