NDLI: Sphingolipid Signaling Reduces Basal P-Glycoprotein Activity in Renal Proximal Tubule

Content Provider	PubMed Central
Author	Miller, David S.
Abstract	P-glycoprotein is an ATP-driven xenobiotic export pump that is highly expressed in barrier and excretory tissues, where it greatly influences drug pharmacokinetics. Recent studies in the blood-brain and spinal cord barriers identified a sphingolipid-based signaling pathway that regulates basal activity of P-glycoprotein. Here we use an established comparative renal model that permits direct measurement of P-glycoprotein activity to determine whether such signaling occurs in another tissue, killifish renal proximal tubule. Isolated killifish tubules exposed to 0.01–1.0 μM sphingosine-1-phosphate (S1P) exhibited a profound decrease in P-glycoprotein transport activity, measured as specific accumulation of a fluorescent cyclosporine A derivative in the tubule lumen. Loss of activity had a rapid onset and was fully reversible when the S1P was removed. Transport mediated by multidrug resistance-associated protein 2 (Mrp2) or a teleost fish organic anion transporter (Oat) was not affected. S1P effects were blocked by a specific S1P receptor 1 (S1PR1) antagonist and mimicked by a S1PR agonist. Sphingosine also reduced P-glycoprotein transport activity and those effects were blocked by an inhibitor of sphingosine kinase and by the S1PR1 antagonist. These results for a comparative renal model suggest that sphingolipid signaling to P-glycoprotein is not just restricted to the blood-brain and blood–spinal cord barriers, but occurs in other excretory and barrier tissues.
Related Links	http://dx.doi.org/10.1124/jpet.113.210641
Ending Page	464
Page Count	6
Starting Page	459
File Format	PDF
ISSN	15210103
e-ISSN	15210103
Journal	The Journal of Pharmacology and Experimental Therapeutics
Issue Number	3
Volume Number	348
Language	English
Publisher	The American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2014-01-27
Access Restriction	Open
Rights Holder	The American Society for Pharmacology and Experimental Therapeutics
Subject Keyword	Molecular Medicine Pharmacology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Molecular Medicine Pharmacology

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