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Abstract 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.