Accelerated publication - Hetero-concatemeric K(IR)6.X-4/SUR1(4) channels display distinct conductivities but uniform ATP inhibition

K(IR)6.1 and K(IR)6.2 are the pore-forming subunits of K-NDP, the nucleotid e-diphosphate-activated K-ATP channels, and classical K-ATP channels, respe ctively. "Hybrid" channels, in which the structure is predetermined by conc atemerizing K(IR)6.1 and K(IR)6.2, exhibit distinct conductivities specifie d by subunit number and position. Inclusion of one K(IR)6.2 is sufficient t o open K(IR)6.X-X-X-X/SUR1(4) in the absence of nucleotide stimulation thro ugh sulfonylurea receptor-1 (SUR1). ATP inhibited the spontaneous bursting of hybrid channels with an IC50(ATP) similar to 10(-5) M, similar to that o f K(IR)6.2(4)-containing channels. These findings and a transient increase in K-NDP channel activity following rapid wash-out of MgATP suggested that K(IR)6.1 is not ATP-insensitive as previously believed. We propose that SUR -dependent, inhibitory ATP-enhanced interactions of the cytoplasmic domains of both K(IR)6.1 and K(IR)6.2 stabilize a closed form of the M2 bundle in the gating apparatus.