title: Sulfonylurea receptors inhibit the epithelial sodium channel (ENaC) by reducing surface expression.
abstract: In the kidney the epithelial Na+ channel (ENaC) is co-expressed with the sulfonylurea receptor (SUR), an ABC protein that shares a high degree of homology with the cystic fibrosis transmembrane conductance regulator (CFTR) and reportedly modifies ENaC in various preparations. To investigate a possible regulatory relationship between SUR and ENaC, we performed co-expression studies on Xenopus laevis oocytes, which were assayed for amiloride-sensitive currents (DeltaIami). Moreover, a chemiluminescence assay was used to investigate the surface expression of extracellular hemagglutinin-tagged SUR1 (SUR1-HA) or HA-tagged ENaC (ENaC-HA). In oocytes co-injected with SUR1/ENaC (or SUR2B/ENaC) DeltaIami was reduced by congruent with 53% (or congruent with 45%) compared to DeltaIami measured in matched control oocytes injected with ENaC alone. The inhibitory effect of SUR on DeltaIami was preserved in oocytes expressing ENaC with C-terminally truncated subunits. Co-expression of SURs did not confer sensitivity of DeltaIami to diazoxide, pinacidil, tolbutamide, or glibenclamide. ENaC does not facilitate the surface expression of SUR1-HA, which is known to be retained in the endoplasmatic reticulum (ER) by an ER-retention/retrieval signal. SUR1-HAAAA, a mutant that lacks this signal, still inhibits ENaC currents. Chemiluminescence was reduced by congruent with 49% in oocytes co-expressing ENaC-HA/SUR1 compared to that in control oocytes expressing ENaC-HA alone. We conclude that SUR does not interact with ENaC at the level of the plasma membrane but that it inhibits DeltaIami by reducing surface expression of the channel.
authors.affiliation: University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Konstas
authors.forename: A
authors.initials: A
authors.lastname: Bielfeld-Ackermann
authors.forename: C
authors.initials: C
authors.lastname: Korbmacher
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004232:Diuretics; D053503:Epithelial Sodium Channels; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D064233:Sulfonylurea Receptors; D013997:Time Factors; D014044:Tolbutamide / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D018528:ATP-Binding Cassette Transporters; D004232:Diuretics; D053503:Epithelial Sodium Channels; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D049993:Sodium Chloride Symporter Inhibitors; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D020110:Pinacidil; D014044:Tolbutamide; D003981:Diazoxide; D005905:Glyburide