Hetero-concatemeric KIR6.X4/SUR14 channels display distinct conductivities but uniform ATP inhibition.

Abstract KIR6.1 and KIR6.2 are the pore-forming subunits ofK NDP , the nucleotide-diphosphate-activated K ATP channels, and classical K ATP channels, respectively. “Hybrid” channels, in which the structure is predetermined by concatemerizing KIR6.1 and KIR6.2, exhibit distinct conductivities specified by subunit number and position. Inclusion of one KIR6.2 is sufficient to open KIR6.X-X-X-X/SUR14 in the absence of nucleotide stimulation through sulfonylurea receptor-1 (SUR1). ATP inhibited the spontaneous bursting of hybrid channels with an IC50(ATP) ∼10− 5 m, similar to that of KIR6.24-containing channels. These findings and a transient increase in K NDP channel activity following rapid wash-out of MgATP suggested that KIR6.1 is not ATP-insensitive as previously believed. We propose that SUR-dependent, inhibitory ATP-enhanced interactions of the cytoplasmic domains of both KIR6.1 and KIR6.2 stabilize a closed form of the M2 bundle in the gating apparatus.