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

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 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 G_i2α, F-actin and PLCγ1 as facilitatory proteins. P_2x 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.