THE MULTIDRUG-RESISTANCE P-GLYCOPROTEIN MODULATES CELL REGULATORY VOLUME DECREASE

Cell volume is frequently down-regulated by the activation of anion ch annels, The role of cell swelling-activated chloride channels in cell volume regulation has been studied using the patch-clamp technique and a non-invasive microspectrofluorimetric assay for changes in cell vol ume, The rate of activation of these chloride channels was shown regul atory volume decrease hyposmotic solutions, Expression of the human MD R1 or mouse mdr1a genes, but not the mouse mdr1b gene, encoding the mu ltidrug resistance P-glycoprotein (P-gp), increased the rate of channe l activation and the rate of RVD, In addition, P-gp decreased the magn itude of hyposmotic shock required to activate the channels and to eli cit RVD, Tamoxifen selectively inhibited both chloride channel activit y and RVD, No effect on potassium channel activity was elicited by exp ression of P-gp, The data show that, in these cell types, swelling-act ivated chloride channels have a central role in RVD, Moreover, they cl arify the role of P-gp in channel activation and provide direct eviden ce that P-gp, through its effect on chloride channel activation, enhan ces the ability of cells to down-regulate their volume.