The vacuolar H+ adenosine-triphosphatase (v-ATPase) multi-subunit complex is a key regulator of intracellular pH homeostasis. KM91104 is a cell-permeable inhibitor of v-ATPase. In hHSC (human hepatic stellate cells), KM91104 (1 nM and 10 nM; 48 hr) reduced v-ATPase expression and activity. Serum starved hHSC displayed a higher neutral red uptake compared to cells in complete medium reflecting a more acidic pH inside the lysosomes and endosomes. KM91104 (10 nM) in serum free condition reversed this effect as demonstrated by a decreased uptake of neutral red when compared to the control cells. Likewise, treatment with 10 nM KM91104 was followed by a significant decrease in cytosolic pH. Specific inhibition of v-ATPase with KM91104 induced a down-regulation of the HSC fibrogenic gene profile, which coincided with increased lysosomal pH, decreased pHi, activation of AMPK, reduced proliferation, and lower metabolic activity[3].
作用机制
KM91104 specifically targets the interaction between v-ATPase subunit a3 and subunit B2[3].
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