The N-terminus of KIR6.2 limits spontaneous bursting and modulates the ATP-inhibition of KATP channels.
KATP channels are heteromultimers of a sulfonylurea receptor SUR and KIR6.2 with the inward rectifier forming the pore which is regulated by SUR. We have examined the contributions of the cytoplasmic domains of KIR6.2 to control of spontaneous bursting and ATP-inhibition in human SUR1/KIR6.2 KATP channels. Truncations of the N-terminus of KIR6.2 nearly eliminate transitions to interburst closed states without affecting the open or intraburst closed states, thus producing SUR1/DeltaNKIR6.2 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 KIR6.2 can synergistically attenuate the ATP-inhibition. The results identify the N-terminus of KIR6.2 as a determinant of the interburst kinetics of KATP channels and suggest that the two cytoplasmic domains of KIR6.2 participate in ATP-inhibitory gating through distinct mechanisms.
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ababenko@bcm.tmc.edu
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Gonzalez
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Bryan
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019943:Amino Acid Substitution / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000502:physiology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000235:genetics; D017384:Sequence Deletion; D013453:Sulfonylurea Compounds / Q000037:antagonists & inhibitors; D064233:Sulfonylurea Receptors
C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate