Intracellular sphingosine 1-phosphate mediates the increased excitability produced by nerve growth factor in rat sensory neurons

Our previous studies found that nerve growth factor (NGF), via ceramide, enhanced the number of action potentials (APs) evoked by a ramp of depolarizing current in capsaicin-sensitive sensory neurons. Ceramide can be metabolized by ceramidase to sphingosine (Sph), and Sph to sphingosine 1-phosphate...

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Bibliographic Details
Published in:The Journal of physiology 2006-08, Vol.575 (1), p.101-113
Main Authors: Zhang, Y. H., Vasko, M. R., Nicol, G. D.
Format: Article
Language:English
Subjects:
Action Potentials
Animals
Cells, Cultured
Enzyme Inhibitors - pharmacology
Ganglia, Spinal - cytology
Ganglia, Spinal - drug effects
Ganglia, Spinal - enzymology
Lysophospholipids - pharmacology
Male
Nerve Growth Factor - pharmacology
Neurons, Afferent - drug effects
Neurons, Afferent - enzymology
Neuroscience
Patch-Clamp Techniques
Perfusion
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Potassium Channels - drug effects
Potassium Channels - metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction
Sphingosine - analogs & derivatives
Sphingosine - pharmacology
Time Factors
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Summary:Our previous studies found that nerve growth factor (NGF), via ceramide, enhanced the number of action potentials (APs) evoked by a ramp of depolarizing current in capsaicin-sensitive sensory neurons. Ceramide can be metabolized by ceramidase to sphingosine (Sph), and Sph to sphingosine 1-phosphate (S1P) by sphingosine kinase. It is well established that each of these products of sphingomyelin metabolism can act as intracellular signalling molecules. This raises the question as to whether the enhanced excitability produced by NGF was mediated directly by ceramide or required additional metabolism to Sph and/or S1P. Sph applied externally did not affect the neuronal excitability, whereas internally perfused Sph augmented the number of APs evoked by the depolarizing ramp. Furthermore, internally perfused S1P enhanced the number of evoked APs. This sensitizing action of NGF, ceramide and internally perfused Sph was abolished by dimethylsphingosine (DMS), an inhibitor of sphingosine kinase. In contrast, internally perfused S1P enhanced the number of evoked APs in the presence of DMS. These observations support the idea that the metabolism of ceramide/Sph to S1P is critical for the sphingolipid-induced modulation of excitability. Both internally perfused Sph and S1P inhibited the outward K + current by 25–35% for the step to +60 mV. The Sph- and S1P-sensitive currents had very similar current–voltage relations, suggesting that they were likely to be the same. In addition, the Sph-induced suppression of the K + current was blocked by pretreatment with DMS. These findings demonstrate that intracellular S1P derived from ceramide acts as an internal second messenger to regulate membrane excitability; however, the effector system whereby S1P modulates excitability remains undetermined.
ISSN:0022-3751
1469-7793
DOI:10.1113/jphysiol.2006.111575