Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Sphingosine 1-phosphate (S1P): physiology and the effects of S1P receptor modulation. Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Thus, sphingosine-1-phosphate and SphK2 play specific roles in memory functions and FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories.īrinkmann, V.
Sphk2 −/− mice have lower levels of hippocampal sphingosine-1-phosphate, an endogenous HDAC inhibitor, and reduced histone acetylation, and display deficits in spatial memory and impaired contextual fear extinction. FTY720 is also phosphorylated in mice and accumulates in the brain, including the hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning, and rescues memory deficits independently of its immunosuppressive actions. We show that FTY720 enters the nucleus, where it is phosphorylated by sphingosine kinase 2 (SphK2), and that nuclear FTY720-P binds and inhibits class I histone deacetylases (HDACs), enhancing specific histone acetylations. FTY720 (fingolimod), an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking.
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