The N-terminus of K(IR)6.2 limits spontaneous bursting and modulates the ATP-inhibition of K-ATP channels

K-ATP channels are heteromultimers of a sulfonylurea receptor SUR and K(IR) 6.2 with the inward rectifier forming the pore which is regulated by SUR. W e have examined the contributions of the cytoplasmic domains of K(IR)6.2 to control of spontaneous bursting and ATP-inhibition in human SUR1/K(IR)6.2 K-ATP channels. Truncations of the N-terminus of K(IR)6.2 nearly eliminate transitions to interburst closed states without affecting the open or intra burst closed states, thus producing SUR1/Delta NK(IR)6.2 channels with an e xtremely high open probability in the absence of nucleotides. These channel s have a decrease apparent ATP-sensitivity which is consistent with the inv olvement of the N-terminus in a transition to an interburst closed state th at preferentially binds inhibitory ATP. Mutations in both the N- and proxim al C-termini of K(IR)6.2 can synergistically attenuate the ATP-inhibition. The results identify the N-terminus of K(IR)6.2 as a determinant of the int erburst kinetics of K-ATP channels and suggest that the two cytoplasmic dom ains of K(IR)6.2 participate in ATP-inhibitory gating through distinct mech anisms. (C) 1999 Academic Press.