Ca2+ Signaling and Proliferation via Ca2+-Sensing Receptors in Human Hepatic Stellate LX-2 Cells

• Published in: Biological & pharmaceutical bulletin Vol. 45; no. 5; pp. 664 - 667
• Main Authors: Kondo, Rubii, Kawata, Naoki, Suzuki, Yoshiaki, Yamamura, Hisao
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01-05-2022; Japan Science and Technology Agency
• Subjects: Actin; Antagonists; Calcium (extracellular); Calcium signalling; calcium-sensing receptor; Calcium-sensing receptors; Calhex 231; Cell growth; Cell proliferation; Fibrosis; hepatic stellate cell; Liver diseases; LX-2; Molecular modelling; NPS2143; proliferation; Smooth muscle; Stellate cells; Therapeutic targets
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b22-00103

Hepatic stellate cells (HSCs) play a significant role in the development of chronic liver diseases. Hepatic damage activates HSCs and results in hepatic fibrosis. The functions of activated HSCs require an increase in the cytosolic Ca2+ concentration ([Ca2+]cyt). However, the regulatory mechanisms underlying Ca2+ signaling in activated HSCs remain largely unknown. In the present study, functional analyses of Ca2+-sensing receptors (CaSRs) were performed using activated human HSCs, LX-2. Expression analyses revealed that CaSR proteins were expressed in α-smooth muscle actin-positive LX-2 cells. Extracellular Ca2+ restoration (from 0 to 2.2 mM) increased [Ca2+]cyt in these cells. The extracellular Ca2+-induced increase in [Ca2+]cyt was reduced by the CaSR antagonists, NPS2143 and Calhex 231. Furthermore, the growth of LX-2 cells was blocked by NPS2143 and Calhex 231 in concentration-dependent manners (IC50 = 6.0 and 9.5 μM, respectively). LX-2 cell proliferation was also attenuated by NPS2143 and Calhex 231. In conclusion, CaSRs are functionally expressed in activated HSCs and regulate Ca2+ signaling and cell proliferation. The present results provide insights into the molecular mechanisms underlying hepatic fibrosis and will contribute to the development of potential therapeutic targets.