Drugs transported by P-glycoprotein inhibit a 40 pS outwardly rectifying chloride channel.
P-glycoprotein functions as an ATP-dependent pump for a diverse spectrum of compounds. Recently, it has been shown that P-glycoprotein may be bi-functional and act as a chloride channel as well as a pump. The single channel properties of this conductance are unknown, however, as macroscopic, whole cell currents are inhibited by substrates for P-glycoprotein transport, the single channels underlying this response should also be blocked by these compounds. We found that colchicine, vinblastine, daunomycin and verapamil (50 microM) caused block of a 40 pS outwardly-rectifying chloride channel in cells expressing P-glycoprotein. The inhibitory effect of these compounds appeared specific for the 40 pS chloride channel as a large, 300 pS chloride channel found in the same cells was unaffected by addition of drug. These results suggest that the 40 pS chloride channel may be associated with P-glycoprotein expression.
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Division of Cell Biology, Hospital for Sick Children, Toronto, Canada.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000502:physiology*; D003078:Colchicine / Q000378:metabolism / Q000494:pharmacology*; D006224:Cricetinae; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology*; D004351:Drug Resistance; D015640:Ion Channel Gating / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology*; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D018118:Chloride Channels; D008562:Membrane Glycoproteins; D014747:Vinblastine; D014700:Verapamil; D003078:Colchicine; D003630:Daunorubicin