The multidrug resistance P-glycoprotein modulates cell regulatory volume decrease.
Cell volume is frequently down-regulated by the activation of anion channels. 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 volume. The rate of activation of these chloride channels was shown to limit the rate of regulatory volume decrease (RVD) in response to hyposmotic solutions. Expression of the human MDR1 or mouse mdr1a genes, but not the mouse mdr1b gene, encoding the multidrug resistance P-glycoprotein (P-gp), increased the rate of channel activation and the rate of RVD. In addition, P-gp decreased the magnitude of hyposmotic shock required to activate the channels and to elicit RVD. Tamoxifen selectively inhibited both chloride channel activity and RVD. No effect on potassium channel activity was elicited by expression of P-gp. The data show that, in these cell types, swelling-activated chloride channels have a central role in RVD. Moreover, they clarify the role of P-gp in channel activation and provide direct evidence that P-gp, through its effect on chloride channel activation, enhances the ability of cells to down-regulate their volume.
Nuffield Department of Clinical Biochemistry and Imperial Cancer Research Fund Laboratories, John Radcliffe Hospital, University of Oxford, UK.
M A
MA
Valverde
T D
TD
Bond
S P
SP
Hardy
J C
JC
Taylor
C F
CF
Higgins
J
J
Altamirano
F J
FJ
Alvarez-Leefmans
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016466:CHO Cells; D048429:Cell Size; D018118:Chloride Channels / Q000187:drug effects; D006224:Cricetinae; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D009994:Osmolar Concentration; D015221:Potassium Channels / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D013629:Tamoxifen / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018118:Chloride Channels; D015221:Potassium Channels; D013629:Tamoxifen