Les sphingolipides : vecteurs d’agents pathogènes et cause de maladies génétiques

Les sphingolipides (SPL) sont des molécules ubiquitaires indispensables au maintien et au développement des organismes vivants. Ils ne sont pas répartis uniformément le long de la membrane mais regroupés sous forme de microdomaines lipidiques appelés rafts. On a longtemps pensé que les SPL avaient uniquement un rôle structural. On sait maintenant qu’ils jouent aussi un rôle de récepteur et de seconds messagers (intervenant dans des fonctions majeures de la vie cellulaire) et que de nombreuses maladies génétiques (sphingolipidoses) s’expliquent par un dysfonctionnement de leur métabolisme. Après un rappel des propriétés structurales des sphingolipides, cet article fait le point sur les relations entre leur rôle de récepteur et l’entrée d’agents pathogènes dans la cellule ainsi que sur les mécanismes pathologiques des sphingolipidoses.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

Neuronal Conduction of Excitation without Action Potentials Based on Ceramide Production

International audienceBACKGROUND: 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

Sphingolipides et physiologie des ganglions sympathiques prévertébraux

J ai étudié le rôle du céramide dans la physiologie des ganglions sympathiques prévertébraux chez le lapin. Sur une préparation in vitro ganglion isolé, j ai montré que le céramide participe aux propriétés intégratives des neurones ganglionnaires sympathiques en modulant leur activation synaptique nicotinique. Sur une préparation in vitro ganglion-organe, j ai étudié le mécanisme de transfert de l excitation neuronale sans potentiel d action se produisant lors du réflexe gastro-duodénal inhibiteur. J ai montré que le céramide produit par l activation de la sphingomyélinase neutre est à la base de ce mécanisme. Ce transfert d excitation nécessite l intégrité des rafts et l activation en cascade de la séquence de seconds messagers suivante : céramide -> calcium -> NO -> GMPc. Les sphingolipides jouent donc un rôle important dans la physiologie des ganglions prévertébraux. Mes résultats ouvrent des perspectives de recherche dans un domaine fondamental qui est celui du fonctionnement neuronal.AIX-MARSEILLE3-BU Sc.St Jérô (130552102) / SudocSudocFranceF

Conduction nerveuse d’excitation sans potentiel d’action

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