PI3‐kinase/Akt pathway‐regulated membrane transportation of acid‐sensing ion channel 1a/Calcium ion influx/endoplasmic reticulum stress activation on PDGF‐induced HSC Activation

Abstract

Acid‐sensing ion channel 1a (ASIC1a) allows Na + and Ca 2+ flow into cells. It is expressed during inflammation, in tumour and ischaemic tissue, in the central nervous system and non‐neuronal injury environments. Endoplasmic reticulum stress (ERS) is caused by the accumulation of misfolded proteins that interferes with intracellular calcium homoeostasis. Our recent reports showed ASIC1a and ERS are involved in liver fibrosis progression, particularly in hepatic stellate cell (HSC) activation. In this study, we investigated the roles of ASIC1a and ERS in activated HSC. We found that ASIC1a and ERS‐related proteins were up‐regulated in carbon tetrachloride (CCl 4 )‐induced fibrotic mouse liver tissues, and in patient liver tissues with hepatocellular carcinoma with severe liver fibrosis. The results show silencing ASIC1a reduced the expression of ERS‐related biomarkers GRP78, Caspase12 and IREI‐XBP1. And, ERS inhibition by 4‐PBA down‐regulated the high expression of ASIC1a induced by PDGF, suggesting an interactive relationship. In PDGF‐induced HSCs, ASIC1a was activated and migrated to the cell membrane, leading to extracellular calcium influx and ERS, which was mediated by PI3K/AKT pathway. Our work shows PDGF‐activated ASIC1a via the PI3K/AKT pathway, induced ERS and promoted liver fibrosis progression.

Factors and Molecular Mechanisms Influencing the Protein Synthesis, Degradation and Membrane Trafficking of ASIC1a

“…Our previous studies have confirmed that PcTx1 reversed the enhancing effect of extracellular acidification on ASIC1a protein and mRNA expression in articular chondrocytes (Gao et al, 2019;Wu et al, 2019). Similarly, the increased expression and membrane trafficking of ASIC1a induced by PDGF stimulation were inhibited by PcTx1 (Zuo et al, 2019).…”

“…A similar signaling pathway is also involved in the process of platelet-derived growth factor (PDGF), regulating the expression and membrane trafficking of ASIC1a (Zuo et al, 2019). The expression and membrane trafficking of ASIC1a protein were remarkably increased in PDGF-stimulated hepatic stellate cells.…”

“…The expression and membrane trafficking of ASIC1a protein were remarkably increased in PDGF-stimulated hepatic stellate cells. However, these effects could be prevented by inhibiting activation of the PI3K/Akt signaling pathway with the inhibitor LY294002 (Zuo et al, 2019), revealing that PDGF stimulated the expression and membrane trafficking of ASIC1a via the PI3K/Akt pathway.…”

ASIC1a regulates miR‐350/SPRY2 by N 6 ‐methyladenosine to promote liver fibrosis

“…How ASIC1a regulates m 6 A modification through METTL3 in liver fibrosis remains to be explored. Activation of ASIC1a channels induces extracellular Ca 2+ influx 13 . Another study found that the protein SUMO level is affected by changes in intracellular calcium levels 68 .…”

Targeting Hepatic Stellate Cells for the Treatment of Liver Fibrosis by Natural Products: Is It the Dawning of a New Era?

“…Animal studies have shown the critical role of the mitogen PDGF as well as its receptor PDGF receptor-b (PDGFRb) in HSC proliferation and migration (Wong et al, 1994;Kostallari et al, 2018). The extent of inflammation so as fibrosis is correlated with the expression of PDGF in patients with chronic liver diseases (Zuo et al, 2019). Interestingly, the mRNA expression of PDGFRb was confirmed in both quiescent and activated HSCs, but protein production was mainly limited to the activated cells (Henderson et al, 2013).…”