BK_Caチャネル阻害薬は肝星細胞の増殖を抑制する

抄録

Hepatic stellate cells are liver-specific pericytes that play central roles in the development of liver fibrosis. During liver injury, hepatic stellate cells transdifferentiate from the quiescent phenotype into the myofibroblast-like phenotype, resulting in high proliferation and extracellular matrix production. Large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels are expressed in many types of tissues and involved in the regulation of membrane potential, intracellular Ca²⁺ concentration, and cell proliferation. However, the involvement of BK_Ca channels on liver fibrosis remains unclear. In this study, we investigated the pathophysiological roles of BK_Ca channels in a human hepatic stellate cell line, LX-2. The mRNA expression analysis revealed that LX-2 cells highly expressed the α subunit of BK_Ca channels. In LX-2 cells, extracellular Ca²⁺ restoration in the presence of thapsigargin induced store-operated Ca²⁺ (SOC) entry, which potentially mediated by Orai/STIM channels. The SOC entry was significantly reduced by a specific inhibitor of BK_Ca channels, paxilline. In addition, the proliferation of LX-2 cells was clearly attenuated by paxilline. These results suggest that BK_Ca channels are functionally expressed in LX-2 cells and contribute to cell proliferation by regulating intracellular Ca²⁺ signaling.