TY - JOUR
T1 - Multifaceted roles of sphingosine-1-phosphate
T2 - How does this bioactive sphingolipid fit with acute neurological injury?
AU - Singh, Indrapal N.
AU - Hall, Edward D.
PY - 2008/5/15
Y1 - 2008/5/15
N2 - 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.
AB - 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.
KW - Mitochondria
KW - Sphingosine kinase
KW - Sphingosine-1-phosphate
KW - Spinal cord injury
KW - Traumatic brain injury
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U2 - 10.1002/jnr.21586
DO - 10.1002/jnr.21586
M3 - Review article
C2 - 18058948
AN - SCOPUS:43149110826
SN - 0360-4012
VL - 86
SP - 1419
EP - 1433
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
IS - 7
ER -