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1 Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; 3 Department of Pharmacology and Toxicology, University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands; 4 Department of Cell Biology and Anatomy and Marine Biomedicine and Environmental Science Program, Medical University of South Carolina, Charleston, South Carolina 29425; and 2 Mount Desert Island Biological Laboratory, Salsbury Cove, Maine 04672
We examined endothelin-1 (ET-1) regulation of the xenobiotic efflux pump, multidrug resistance-associated protein isoform 2 (MRP2), in intact dogfish shark rectal salt gland tubules using a fluorescent substrate sulforhodamine 101 and confocal microscopy. Subnanomolar to nanomolar concentrations of ET-1 rapidly reduced the cell-to-lumen transport of sulforhodamine 101. These effects were prevented by an ETB receptor antagonist but not by an ETA receptor antagonist. Immunostaining with an antibody to mammalian ETB receptors showed specific localization to the basolateral membrane of the shark rectal gland epithelial cells. ET-1 effects on transport were blocked by a protein kinase C (PKC)-selective inhibitor, implicating PKC in ET-1 signaling. A protein kinase A (PKA)-selective inhibitor had no effect. Forskolin reduced luminal accumulation of sulforhodamine 101, but inhibition of PKA did not block the forskolin effect. Consistent with this observation, a cAMP analog that does not activate PKA reduced luminal accumulation of sulforhodamine 101. These results indicate that shark rectal gland transport on MRP2 is regulated by ET acting through an ETB receptor and PKC. In addition, cAMP affects transporter function through a PKA-independent mechanism, possibly by competition for transport.
endothelin-1; multidrug resistance-associated protein isoform 2; protein kinase C
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