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Signal Transduction and Modulation

開催日 2014/9/12
時間 14:00 - 15:00
会場 Poster / Exhibition(Event Hall B)

Fingolimod regulates PKA/DARPP-32 signaling in striatal medium spiny neurons via neuronal sphingosine-1-phosphate receptor mechanisms

  • P2-060
  • 上松 謙 / Ken Uematsu:1,2,3 森田 喜一郎 / KIICHIRO MORITA:1,2 内村 直尚 / NAOHISA UCHIMURA:1,2 西 昭徳 / AKINORI NISHI:3 
  • 1:久留米大学高次脳疾患研究所 / Cognitive and Mol. Res. Inst. of Brain Diseases, Kurume Univ. Sch. of Med. 2:久留米大学・医・神経精神科 / Dept. Neuropsychi., Kurume Univ. Sch. of Med. 3:久留米大学・医・薬理学 / Dept. Pharmacol., Kurume Univ. Sch. of Med. 

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates critical cellular processes such as proliferation, survival and migration as well as angiogenesis, allergic responses and immune responses. S1P exerts its function by activating S1P receptors (S1PRs). Fingolimod is an agonist of S1PRs and a new oral drug for multiple sclerosis. There are five S1PR subtypes: S1P 1R, S1P 2R, S1P 3R, S1P 4R and S1P 5R. Fingolimod binds to all S1PR subtypes except S1P 2R. It has been reported that S1PRs are expressed in many cell types including neurons, astrocytes, microglia and oligodendrocytes in the brain. There are few reports about a possible role of S1P and fingolimod in neurons. In this study, we investigated the effect of S1P and fingolimod on cAMP/PKA signaling in mouse striatal slices by monitoring the phosphorylation states of an intracellular phospho-protein, dopamine- and cAMP-regulated phosphoprotein of M r 32 kDa (DARPP-32), in which Thr34 is phosphorylated by PKA. Treatment of slices with S1P (10 μM) or a selective S1P1R agonist, SEW2871 (10 μM), increased DARPP-32 Thr34 phosphorylation at 1 min of incubation by 2-3-fold. Treatment of slices with fingolimod (100 nM) increased DARPP-32 Thr34 phosphorylation at 30 sec by 2-fold and decreased at 30 min by 0.6-fold. The increase in DARPP-32 phosphorylation induced by S1P was abolished by pre-treatment with a dopamine D2 receptor agonist, quinpirole, or an adenosine A2A receptor antagonist, ZM241385. Analysis using D1-DARPP-32-Flag/D2-DARPP-32-Myc transgenic mice revealed that activation of S1PRs by S1P increased DARPP-32 Thr34 phosphorylation in D2-type/striatopallidal neurons, but not in D1-type/striatonigral neurons. Thus, fingolimod likely activates cAMP/PKA signaling via activation of S1PRs selectively in D2-type/striatopallidal neurons, and the effect is under control of D2 and A2A receptors.

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