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.

Inositol 1,4,5-trisphosphate receptor type 3 plays a protective role in hepatocytes during hepatic ischemia-reperfusion injury

“…The mechanism by which ITPR3 exerts a protective effect in ischemia-reperfusion injury is unclear. ITPR plays an important role in apoptosis because it regulates transmission of Ca 2+ from the ER to mitochondria, and mitochondrial Ca 2+ overload by this route induces formation of permeability transition pores in the mitochondrial membrane, which then leads to apoptosis (26). ITPR-mediated mitochondrial Ca 2+ signaling has been linked to apoptotic and necrotic cell death in the liver in particular (39,40), and new expression of ITPR3 in hepatocytes has been linked to resistance to apoptotic cell death in hepatocellular carcinoma (13).…”

“…Since ITPR1 and ITPR2 are the Ca 2+ channel isoforms that normally regulate hepatocyte functions (26), we investigated how the de novo ITPR3 expression in hepatocytes would affect Ca 2+ signaling in whole liver. To address this, we performed in vivo Ca 2+ signal measurements using Fluo-4.…”

Transmembrane channel activity in human hepatocytes and cholangiocytes derived from induced pluripotent stem cells

“…Additional gene‐expression analyses were performed to document the relative expression of mature cholangiocyte‐specific markers (Sox9, HNF1β, and ITPR3), an intracellular calcium release channel involved in bicarbonate secretion in bile ducts. [ 33 ] Next, to fully characterize cholangiocyte phenotype of the resulting cells, we evaluated gene expression of functional components within the bile production machinery expressed in the human cholangiocytes. Secretin receptor, Cl − /HCO 3 − anion exchanger 2, aquaporin 1, cholinergic receptor muscarinic 3, and P2Y purinoceptor 1 were expressed in iCho cells at comparable levels to those in human primary cholangiocyte, controls (Figure 2C ).…”

Adaptation to volumetric compression drives hepatoblastoma cells to an apoptosis-resistant and invasive phenotype

“…Regulation of critical liver functions, including cell proliferation, secretion, and apoptosis, depends on calcium 27 . Calcium channels inositol 1,4,5-trisphosphate (InsP3) receptors (ITPRs) are major players in intracellular calcium signaling in both normal and pathological hepatocytes 27–30 .…”

“…Regulation of critical liver functions, including cell proliferation, secretion, and apoptosis, depends on calcium 27 . Calcium channels inositol 1,4,5-trisphosphate (InsP3) receptors (ITPRs) are major players in intracellular calcium signaling in both normal and pathological hepatocytes 27–30 . The crosstalk between mitochondria and endoplasmic reticulum (ER) through ITPRs, leading to calcium flux, has been identified as a crucial factor in determining senescence 31 and apoptosis 32 - two important targets in cancer.…”