Mrp1 is essential for sphingolipid signaling to p-glycoprotein in mouse blood-brain and blood-spinal cord barriers

J Cereb Blood Flow Metab. 2013 Mar;33(3):381-8. doi: 10.1038/jcbfm.2012.174. Epub 2012 Nov 21.

Abstract

At the blood-brain and blood-spinal cord barriers, P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to central nervous system (CNS) pharmacotherapy. Recently, we showed that signaling through tumor necrosis factor-α (TNF-α), sphingolipids, and sphingosine-1-phosphate receptor 1 (S1PR1) rapidly and reversibly reduced basal P-glycoprotein transport activity in the rat blood-brain barrier. The present study extends those findings to the mouse blood-brain and blood-spinal cord barriers and, importantly, identifies multidrug resistance-associated protein 1 (Mrp1, Abcc1) as the transporter that mediates S1P efflux from brain and spinal cord endothelial cells. In brain and spinal cord capillaries isolated from wild-type mice, TNF-α, sphingosine, S1P, the S1PR agonist fingolimod (FTY720), and its active, phosphorylated metabolite, FTY720P, reduced P-glycoprotein transport activity; these effects were abolished by a specific S1PR1 antagonist. In brain and spinal cord capillaries isolated from Mrp1-null mice, neither TNF-α nor sphingosine nor FTY720 reduced P-glycoprotein transport activity. However, S1P and FTY720P had the same S1PR1-dependent effects on transport activity as in capillaries from wild-type mice. Thus, deletion of Mrp1 alone terminated endogenous signaling to S1PR1. These results identify Mrp1 as the transporter essential for S1P efflux from the endothelial cells and thus for inside-out S1P signaling to P-glycoprotein at the blood-brain and blood-spinal cord barriers.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Biological Transport, Active / drug effects
  • Biological Transport, Active / physiology
  • Blood-Brain Barrier / metabolism*
  • Capillaries / metabolism
  • Endothelial Cells / metabolism
  • Fingolimod Hydrochloride
  • Immunosuppressive Agents / pharmacology
  • Lysophospholipids / genetics
  • Lysophospholipids / metabolism*
  • Mice
  • Mice, Knockout
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Propylene Glycols / pharmacology
  • Receptors, Lysosphingolipid / antagonists & inhibitors
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Sphingolipids / genetics
  • Sphingolipids / metabolism*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / genetics
  • Sphingosine / metabolism
  • Sphingosine / pharmacology
  • Sphingosine-1-Phosphate Receptors
  • Spinal Cord / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Immunosuppressive Agents
  • Lysophospholipids
  • Multidrug Resistance-Associated Proteins
  • Nerve Tissue Proteins
  • Propylene Glycols
  • Receptors, Lysosphingolipid
  • S1pr1 protein, mouse
  • Sphingolipids
  • Sphingosine-1-Phosphate Receptors
  • Tumor Necrosis Factor-alpha
  • sphingosine 1-phosphate
  • Fingolimod Hydrochloride
  • Sphingosine
  • multidrug resistance-associated protein 1