Ceramide, a putative second messenger for nerve growth factor, modulates the TTX-resistant Na(+) current and delayed rectifier K(+) current in rat sensory neurons.

摘要: Because nerve growth factor (NGF) is elevated during inflammation and known to activate the sphingomyelin signalling pathway, we examined whether NGF its putative second messenger, ceramide, could modulate excitability of capsaicin-sensitive adult embryonic sensory neurons. Using whole-cell patch-clamp recording technique, exposure isolated neurons either 100 ng ml−1 or 1 μM N-acetyl sphingosine (C2-ceramide) produced a 3- 4-fold increase in number action potentials (APs) evoked by ramp depolarizing current time-dependent manner. Intracellular perfusion with bacterial sphingomyelinase (SMase) also increased APs suggesting that release native ceramide enhanced neuronal excitability. Glutathione, an inhibitor neutral SMase, completely blocked NGF-induced augmentation AP firing, whereas dithiothreitol, acidic was without effect. In presence glutathione NGF, exogenous still APs, indicating sensitizing downstream NGF. To investigate mechanisms for membrane currents were examined. Both facilitated peak amplitude TTX-resistant sodium (TTX-R INa) approximately 1.5-fold shifted activation more hyperpolarized voltages. addition, suppressed outward potassium (IK) ≈35 %. Ceramide reduced IK concentration-dependent Isolation NGF- ceramide-sensitive indicates they delayed rectifier types IK. The inflammatory prostaglandin, PGE2, additional suppression after (≈35 %), these agents might act on different targets. Thus, our findings indicate pro-inflammatory agent, can rapidly enhance This sensitization probably mediated pathway liberate ceramide(s), wherein appears be messenger involved modulating