Inositol 1,4,5-trisphosphate receptor in the liver: Expression and function

Abstract

The liver is a complex organ that performs several functions to maintain homeostasis. These functions are modulated by calcium, a second messenger that regulates several intracellular events. In hepatocytes and cholangiocytes, which are the epithelial cell types in the liver, inositol 1,4,5-trisphosphate (InsP₃) receptors (ITPR) are the only intracellular calcium release channels. Three isoforms of the ITPR have been described, named type 1, type 2 and type 3. These ITPR isoforms are differentially expressed in liver cells where they regulate distinct physiological functions. Changes in the expression level of these receptors correlate with several liver diseases and hepatic dysfunctions. In this review, we highlight how the expression level, modulation, and localization of ITPR isoforms in hepatocytes and cholangiocytes play a role in hepatic homeostasis and liver pathology.

Keywords: Calcium signaling; Hepatocytes and cholangiocytes; Inositol 1,4,5-trisphosphate receptor; Liver.

Figure 1

The hepatic lobule-the microscopic functional structure of the liver. The hepatocytes are arranged in cordon, connecting the central vein to the portal triad, which is formed by a hepatic artery, a portal vein and a bile duct. The other represented cell types are: Kupffer cell, resident macrophages responsible for the immunologic response in the liver, and cholangiocytes which form the bile duct that transport bile to the gallbladder.

Figure 2

The microenvironment in the hepatic lobules. A: Perfusion with fluorescein isothiocyanate albumin shows that the blood flow arrives in the liver by portal vein, passes throughout the sinusoidal space, and drains into the central vein; B: Due to this blood flux, different zones of oxygenation are observed: zone 1, closer to portal vein, is the most highly oxygenated and zone 3 is the least oxygenated. zone 2 is intermediary. The direction of bile flux is opposite to that of blood flow. The bile acids excreted by the hepatocytes go to the bile duct through the biliary canaliculous.

Figure 3

Calcium signaling. After the ligation of an agonist to its receptor, here represent by the ligation of acetylcholine to muscarinic acetylcholine receptor, phospholipase C is activated and produces 1,4,5 inositol triphosphate. The inositol 1,4,5-trisphosphate binds its receptor, inositol 1,4,5-trisphosphate receptor, that is expressed mainly along the endoplasmic reticulum, leading to Ca²⁺ release into the cytosol. Ach: Acetylcholine; M3R: Muscarinic acetylcholine receptor; PLC: Phospholipase C; InsP₃: Inositol 1,4,5-trisphosphate; ITPR: Inositol 1,4,5-trisphosphate receptor; ER: Endoplasmic reticulum.

Figure 4

Inositol 1,4,5-trisphosphate receptor structure. A: Linear structure of inositol 1,4,5-trisphosphate receptor (ITPR). The inositol 1,4,5-trisphosphate (InsP₃)-binding domain is located on the N-terminal region and the pore channel is on the C-terminal region. The receptor spans organelle membrane six times; B: Tridimensional view of ITPR showing that the receptor is formed by a 4 single chain. It is necessary that four InsP₃ molecules bind to the receptor to lead the calcium releases by a pore of the channel. The tridimensional structure was adapted from Molecular Modeling Database (National Center for Biotechnology Information). ER: Endoplasmic reticulum; ITPR: Inositol 1,4,5-trisphosphate receptor; NR: Nucleoplasmic reticulum.

Figure 5

Inositol 1,4,5-trisphosphate receptors in the liver: Expression and functions. This figure summarizes, in green, Inositol 1,4,5-trisphosphate receptor (ITPR) isoform expression in hepatocytes and cholangiocytes under physiological condition, and in red the expression level and function of each ITPR isoform in liver diseases. ITPR1: ITPR isoform 1; ITPR2: ITPR isoform 2; ITPR3: ITPR isoform 3; ER: Endoplasmic reticulum; NAFLD: Non-alcoholic fatty liver disease; HCC: Hepatocellular carcinoma.