title: Hydrogen sulfide as an allosteric modulator of ATP-sensitive potassium channels in colonic inflammation.
abstract: The ATP-sensitive potassium channel (K(ATP)) in mouse colonic smooth muscle cell is a complex containing a pore-forming subunit (Kir6.1) and a sulfonylurea receptor subunit (SUR2B). These channels contribute to the cellular excitability of smooth muscle cells and hence regulate the motility patterns in the colon. Whole-cell voltage-clamp techniques were used to study the alterations in K(ATP) channels in smooth muscle cells in experimental colitis. Colonic inflammation was induced in BALB/C mice after intracolonic administration of trinitrobenzene sulfonic acid. K(ATP) currents were measured at a holding potential of -60 mV in high K(+) external solution. The concentration response to levcromakalim (LEVC), a K(ATP) channel opener, was significantly shifted to the left in the inflamed smooth-muscle cells. Both the potency and maximal currents induced by LEVC were enhanced in inflammation. The EC(50) values in control were 6259 nM (n = 10) and 422 nM (n = 8) in inflamed colon, and the maximal currents were 9.9 ± 0.71 pA/pF (60 μM) in control and 39.7 ± 8.8 pA/pF (3 μM) after inflammation. As was seen with LEVC, the potency and efficacy of sodium hydrogen sulfide (NaHS) (10-1000 μM) on K(ATP) currents were significantly greater in inflamed colon compared with controls. In control cells, pretreatment with 100 µM NaHS shifted the EC(50) for LEV-induced currents from 2838 (n = 6) to 154 (n = 8) nM. Sulfhydration of sulfonylurea receptor 2B (SUR2B) was induced by NaHS and colonic inflammation. These data suggest that sulfhydration of SUR2B induces allosteric modulation of K(ATP) currents in colonic inflammation.
authors.affiliation: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0524, USA.
authors.forename: Aravind R
authors.initials: AR
authors.lastname: Gade
authors.forename: Minho
authors.initials: M
authors.lastname: Kang
authors.forename: Hamid I
authors.initials: HI
authors.lastname: Akbarali
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000494:Allosteric Regulation; D000818:Animals; D003092:Colitis / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D019806:Cromakalim / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000378:metabolism*; D015640:Ion Channel Gating; D054086:KATP Channels / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; C577511:Abcc9 protein, mouse; D054086:KATP Channels; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013440:Sulfides; D064233:Sulfonylurea Receptors; C092520:uK-ATP-1 potassium channel; D019806:Cromakalim; C025451:sodium bisulfide; D006862:Hydrogen Sulfide