Two regions of sulfonylurea receptor specify the spontaneous bursting and ATP inhibition of K-ATP channel isoforms

K-ATP channels are heteromultimers of K(IR)6.2 and a sulfonylurea receptor, SUR, an ATP binding cassette (ABC) protein with several isoforms. K(IR)6.2 forms a channel pore whose spontaneous activity and ATP sensitivity are mo dulated by the receptor via an unknown interaction(s), Side by side compari son of single-channel kinetics and steady-state ATP inhibition of human bet a-cell, SUR1/K(IR)6.2, versus cardiac, SUR2A/K(IR)6.2 channels demonstrate that the latter have a greater mean burst duration and open probability in the absence of nucleotides and similar to 4-fold higher IC50(ATP). We have used matched chimeras of SUR1 and SUR2A to show that the kinetics, which de termine the maximal open probability (Po-max), and the ATP sensitivity are functionally separable and to identify the two segments of SUR responsible for these isoform differences. A region within the first five transmembrane domains specifies the interburst kinetics, whereas a C-terminal segment de termines the sensitivity to inhibitory ATP, The separable effects of SUR on ATP inhibition and channel kinetics implies that the cytoplasmic C terminu s of SUR either directly modulates the affinity of a weak ATP binding site on the inward rectifier or affects linkage between the binding site and the gate. This is the first identification of parts of an ABC protein that int eract with an ion channel subunit to modulate the spontaneous activity and ATP sensitivity of the heteromeric channel.