Neuronal conduction of excitation without action potentials based on ceramide production.

BACKGROUND: Action potentials are the classic mechanism by which neurons convey a state of excitation throughout their length, leading, after synaptic transmission, to the activation of other neurons and consequently to network functioning. Using an in vitro integrated model, we found previously that peripheral networks in the autonomic nervous system can organise an unconventional regulatory reflex of the digestive tract motility without action potentials. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we used combined neuropharmacological and biochemical approaches to elucidate some steps of the mechanism that conveys excitation along the nerves fibres without action potentials. This mechanism requires the production of ceramide in membrane lipid rafts, which triggers in the cytoplasm an increase in intracellular calcium concentration, followed by activation of a neuronal nitric oxide synthase leading to local production of nitric oxide, and then to guanosine cyclic monophosphate. This sequence of second messengers is activated in cascade from rafts to rafts to ensure conduction of the excitation along the nerve fibres. CONCLUSIONS/SIGNIFICANCE: Our results indicate that second messengers are involved in neuronal conduction of excitation without action potentials. This mechanism represents the first evidence-to our knowledge-that excitation is carried along nerves independently of electrical signals. This unexpected ceramide-based conduction of excitation without action potentials along the autonomic nerve fibres opens up new prospects in our understanding of neuronal functioning.

Presynaptic GABA-A receptors prevent depression of nicotinic transmission in rabbit coeliac ganglion neurones.

We investigated the involvement of GABA-A receptors in the modulation of the nicotinic transmission of central origin in isolated rabbit coeliac ganglia. Our study was performed in vitro and the electrical activity of the ganglionic neurones was recorded using intracellular recording techniques. During iterative stimulation of the splanchnic nerves, the synaptic action potential probability decreased gradually, indicating a depression of the nicotinic activation. Pharmacological agents acting at GABA-A receptors modulated the action potential probability during the train of pulses. Muscimol (a GABA-A receptor agonist), diazepam (a benzodiazepine site agonist) and 1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (a GABA uptake blocker) increased this probability. Conversely, gabazine or bicuculline (two GABA-A receptor antagonists), picrotoxin (a picrotoxin site agonist) and flumazenil (a benzodiazepine site antagonist) reduced it. These results demonstrate that endogenous GABA, released during the train of pulses, facilitates the central nicotinic activation of the ganglionic neurones by acting on GABA-A receptors. Muscimol also reduced the amplitude ratio of excitatory postsynaptic potentials triggered during the paired-pulse protocol without any change in postsynaptic properties. This result is consistent with a presynaptic action of GABA-A receptors. Our study shows that presynaptic GABA-A receptors facilitate the central nicotinic activation of prevertebral ganglionic neurones and thus play a novel role in the integrative properties of the sympathetic prevertebral ganglia.

[Sphingolipids, vehicle for pathogenic agents and cause of genetic diseases]. / Les sphingolipides: vecteurs d'agents pathogènes et cause de maladies génétiques.

Sphingolipids are present in all eukaryotic cells and share a sphingoid base : sphingosine. They were first discovered in 1884 and for a long time they were thought to participate to membrane structure only. Recently it has been established that they are mainly located in particular areas of the membrane called rafts which are signalling platforms. It has also been demonstrated that sphingolipids are receptors and second messengers. They play a crucial role in cellular functioning and are necessary to maintenance and developing of living organisms. However due to their receptor properties, they are also gateway for penetration of pathogenic agents such as virus (Ebola, HIV) or toxins (botulinium, tetanus). These agents first bind to glycosphingolipids or proteins mainly located in rafts. The complex so formed is required for the crossing of the membrane by the pathogenic agent. Sphingolipids metabolism is regulated by numerous enzymes. A failure in the activity of one of them induces an accumulation of sphingolipids known as sphingolipidoses. These are genetic diseases having severe consequences for the survival of the organism. The precise mechanisms of the sphingolipidoses are still mainly unknown which explains why few therapeutic strategies are available. These particular properties of lipids rafts and sphingolipids explain why a growing number of studies in the medical and scientific fields are devoted to them.