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+(KATP) channel activity recorded from skeletal muscle of K+-depleted rats. Patch-clamp and gene expression measurements of KATP channel subunits were performed. A down-regulation of the KATP 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 KATP channel currents of −69.5% in K+-depleted rats was observed. The Kir6.2/SUR2A-B agonist cromakalim showed similar potency in activating the KATP channels of normokalaemic and K+-depleted rats but reduced efficacy in K+-depleted rats. The Kir6.2/SUR1-2B agonist diazoxide activated KATP channels in normokalaemic and K+-depleted rats with equal potency and efficacy. The down-regulation of the Kir6.2 explains the reduced KATP 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.