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- W2059823498 abstract "The epithelial sodium channel (ENaC) regulates the sodium reabsorption in the collecting duct principal cells of the nephron. ENaC is mainly regulated by hormones such as aldosterone and vasopressin, but also by serine proteases, Na+ and divalent cations. The crystallization of an ENaC/Deg member, the Acid Sensing Ion Channel, has been recently published but the pore-lining residues constitution of ENaC internal pore remains unclear. It has been reported that mutation aS589C of the selectivity filter on the aENaC subunit, a three residues G/SxS sequence, renders the channel permeant to divalent cations and sensitive to extracellular Cd2+. We have shown in the first part of my work that the side chain of aSer589 residue is not pointing toward the pore lumen, permitting the Cd2+ to permeate through the ion pore and to coordinate with a native cysteine, gCys546, located in the second transmembrane domain of the gENaC subunit. In a second part, we were interested in the sulfhydryl-reagent intracellular inhibition of ENaC-mediated Na+ current. Kellenberger et al. have shown that ENaC is rapidly and reversibly inhibited by internal sulfhydryl reagents underlying the involvement of intracellular cysteines in the internal regulation of ENaC. We set up a new approach comprisinga Substituted Cysteine Analysis Method (SCAM) using intracellular MTSEA-biotin perfusion coupled to functional and biochemical assays. We were thus able to correlate the cysteine-modification of ENaC by methanethiosulfonate (MTS) and its effect on sodium current. This allowed us to determine the amino acids that are accessible to intracellular MTS and the one important for the inhibition of the channel.RESUME :Le canal epithelial sodique ENaC est responsable de la reabsorption du sodium dans les cellules principales du tubule collecteur renal. Ce canal est essentiellement regule par voie hormonale via l'aldosterone et la vasopressine mais egalement par des serines proteases, le Na+ lui-meme et certains cations divalents. La cristallisation du canal sodique sensible au pH acide, ASIC, un autre membre de la famille ENaC/Deg, a ete publiee mais les acides amines constituant le pore interne d'ENaC restent indetermines. Il a ete montre que la mutation aS589C du filtre de selectivite de la sous-unite aENaC permet le passage de cations divalents et l'inhibition du canal par le Cd2+ extracellulaire. Dans un premier temps, nous avons montre que la chaine laterale de la aSer589 n'est pas orientee vers l'interieur du pore, permettant au Cd2+ de traverser le canal et d'interagir avec une cysteine native du second domaine transrnembranaire de la sous-unite γENaC, γCys546. Dans un second temps, nous nous sommes interesses au mecanisme d'inhibition d'ENaC par les reactifs sulfhydryl internes. Kellenberger et al. ont montre l'implication de cysteines intracellulaires dans la regulation interne d'ENaC par les reactifs sulfhydryl. Nous avons mis en place une nouvelle approche couplant la methode d'analyse par substitution de cysteines (SCAM) avec des perfusions intracellulaires de MTSEAbiotine. Ainsi, nous pouvons meure en correlation les modifications des cysteines d'ENaC par les reactifs methanethiosulfonates (MTS) avec leur effet sur le courant sodique, et donc mettre en evidence les acides amines accessibles aux MTS intracellulaires et ceux qui sont importants dans la fonction du canal." @default.
- W2059823498 created "2016-06-24" @default.
- W2059823498 creator A5051823523 @default.
- W2059823498 date "2009-01-01" @default.
- W2059823498 modified "2023-09-27" @default.
- W2059823498 title "Role of intracellular cysteines in ENaC function" @default.
- W2059823498 hasPublicationYear "2009" @default.
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