title: Reduced expression of Kir6.2/SUR2A subunits explains KATP deficiency in K+-depleted rats.
abstract: We investigated on the mechanism responsible for the reduced ATP-sensitive K(+)(K(ATP)) channel activity recorded from skeletal muscle of K(+)-depleted rats. Patch-clamp and gene expression measurements of K(ATP) channel subunits were performed. A down-regulation of the K(ATP) channel subunits Kir6.2(-70%) and SUR2A(-46%) in skeletal muscles of K(+)-depleted rats but no changes in the expression of Kir6.1, SUR1 and SUR2B subunits were observed. A reduced K(ATP) channel currents of -69.5% in K(+)-depleted rats was observed. The Kir6.2/SUR2A-B agonist cromakalim showed similar potency in activating the K(ATP) channels of normokalaemic and K(+)-depleted rats but reduced efficacy in K(+)-depleted rats. The Kir6.2/SUR1-2B agonist diazoxide activated K(ATP) channels in normokalaemic and K(+)-depleted rats with equal potency and efficacy. The down-regulation of the Kir6.2 explains the reduced K(ATP) channel activity in K(+)-depleted rats. The lower expression of SUR2A explains the reduced efficacy of cromakalim; preserved SUR1 expression accounts for the efficacy of diazoxide. Kir6.2/SUR2A deficiency is associated with impaired muscle function in K(+)-depleted rats and in hypoPP.
authors.affiliation: Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, via Orabona no 4, 70120 Bari, Italy. dtricarico@farmbiol.uniba.it
authors.forename: Domenico
authors.initials: D
authors.lastname: Tricarico
authors.forename: Antonietta
authors.initials: A
authors.lastname: Mele
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Lundquist
authors.forename: Reshma R
authors.initials: RR
authors.lastname: Desai
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: Diana
authors.initials: D
authors.lastname: Conte Camerino
mesh_terms: D000818:Animals; D019806:Cromakalim / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D020514:Hypokalemic Periodic Paralysis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D054086:KATP Channels / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011191:Potassium Deficiency / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D012508:Sarcolemma / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D000099161:Kcnj11 Channel