The N-terminus of KIR6.2 limits spontaneous bursting and modulates the ATP-inhibition of KATP 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. We 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 intraburst closed states, thus producing SUR1/Delta NK(IR)6.2 channels with an extremely high open probability in the absence of nucleotides. These channels have a decrease apparent ATP-sensitivity which is consistent with the involvement of the N-terminus in a transition to an interburst closed state that preferentially binds inhibitory ATP. Mutations in both the N- and proximal 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 interburst kinetics of K-ATP channels and suggest that the two cytoplasmic domains of K(IR)6.2 participate in ATP-inhibitory gating through distinct mechanisms. (C) 1999 Academic Press.