上皮細胞のイオン輸送と分化に関与したカルシウム 活性化ク口ライドチヤネル関連分子の機能発現

摘要

CI- -permeable channels and transporters expressed on the cell membranes of various mammalian cell types play pivotal roles in the transport of electrolytes and water, pH regulation, cell volume and membrane excitability, and are therefore expected to be useful molecular targets for drug discovery. Both TMEM16A (a possible candidate for Ca2+-regulated Cl~ channels recently identified) and cystic fibrosis transmembrane conductance regulator (CFTR) (or cAMP-regulated CI- channels) have been known to be involved in CI- secretion and reabsorption in the rat salivary gland. Crosstalk between two types of regulatory pathways through these two types of channels has also been described. Previously, we demonstrated that CLCA, a Ca2+-activated CI- channel modulator, was involved in CI- absorption in rat salivary ducts. In addition to Ca2+ ， basal NF-/cB activity in a mouse keratinocyte line was shown to be involved in the transcriptional regulation of CLCA. Conversely, a truncated isoform of CLCA was found in undifferentiated epithelial cells present in the rat epidermal basal layers. Under regulation by Ca2+ and PKC, the surface expression of ySi-integrin and cell adhesion were decreased in the CLCA-overexpressing cells. Knockdown of this isoform elevated the expression of beta1-integrin in rat epidermis in vivo. These results indicate that the specific differentiation-dependent localization of CLCA, and transcriptional regulation through Ca2+, are likely to affect ion permeability and the adhesive potential of epithelial cells. In summary, these types of Cl~ channels and their modulators may function in a coordinated manner in regulating the functions of epithelial cells under different physiological conditions.