Multifaceted roles of sphingosine-1-phosphate: How does this bioactive sphingolipid fit with acute neurological injury?

Indrapal N. Singh, Edward D. Hall

Research output: Contribution to journalReview articlepeer-review

28 Scopus citations

Abstract

Sphingosine-1-phosphate (Sph-1-P) is an essential bioactive sphingolipid metabolite that has currently become the focus of intense interest. Sph-1-P is generated by the enzyme sphingosine kinase (SphK) in response to diverse stimuli, including growth factors, cytokines, and G-protein-coupled receptor (GPCR) agonists. Its precursor, sphingosine (Sph), is produced from the precursor ceramide (Cer) via a ceramidase (CDase) that is released from membrane sphingomyelin (SPM) by sphingomyelinases (SMase). Accumulating evidence indicates that Sph-1-P is the key regulatory lipid involved in the metabolism of sphingolipids and is involved in the control of numerous aspects of cell physiology, including mitogenesis, differentiation, migration, and apoptosis. These actions of Sph-1-P are mediated by a family of high-affinity S1P receptors, named S1P1-5, which are coupled differentially via Gi, Gq, G12/13, and Rho to multiple effector systems, including adenylate cyclase, phospholipases C (PLC) and D (PLD), extracellular-signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and nonreceptor tyrosine kinases. In this Review, we accumulate available evidence implying that sphingolipid signaling may represent a novel neuroprotective target to counteract the pathophysiology of acute brain and spinal cord injury in regard to apoptotic cell death mechanisms, mitochondrial dysfunction, lipid hydrolysis, and oxidative damage mechanisms. Furthermore, we discuss how Sph-1-P agonist approaches might be expected to increase the resistance of the central nervous system to injury by promoting neurotrophic activity, neurogenesis, and angiogenesis. On the other hand, antagonists of certain Sph-1-P-related activity might possess proregenerative effects via promotion of neurite growth and inhibition of astrogliotic scarring.

Original languageEnglish
Pages (from-to)1419-1433
Number of pages15
JournalJournal of Neuroscience Research
Volume86
Issue number7
DOIs
StatePublished - May 15 2008

Keywords

  • Mitochondria
  • Sphingosine kinase
  • Sphingosine-1-phosphate
  • Spinal cord injury
  • Traumatic brain injury

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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