Reduced expression of Kir6.2/SUR2A subunits explains KATP deficiency in K+-depleted rats.
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.
Tricarico
Domenico
D
Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, via Orabona no 4, 70120 Bari, Italy. dtricarico@farmbiol.uniba.it
Mele
Antonietta
A
Liss
Birgit
B
Ashcroft
Frances M
FM
Lundquist
Andrew L
AL
Desai
Reshma R
RR
George
Alfred L
AL
Conte Camerino
Diana
D
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