XB-ART-36166J Physiol October 15, 2006; 576 (Pt 2): 379-89.
The N-terminal transmembrane domain (TMD0) and a cytosolic linker (L0) of sulphonylurea receptor define the unique intrinsic gating of KATP channels.
ATP-sensitive potassium (K(ATP)) channels comprise four pore-forming Kir6 and four regulatory sulphonylurea receptor (SUR) subunits. SUR, an ATP-binding cassette protein, associates with Kir6 through its N-terminal transmembrane domain (TMD0). TMD0 connects to the core domain of SUR through a cytosolic linker (L0). The intrinsic gating of Kir6.2 is greatly altered by SUR. It has been hypothesized that these changes are conferred by TMD0. Exploiting the fact that the pancreatic (SUR1/Kir6.2) and the cardiac (SUR2A/Kir6.2) K(ATP) channels show different gating behaviours, we have tested this hypothesis by comparing the intrinsic gating of Kir6.2 with the last 26 residues deleted (Kir6.2Delta26) co-expressed with SUR1, S1-TMD0, SUR2A and S2-TMD0 at -40 and -100 mV (S is an abbreviation for SUR; TMD0/Kir6.2Delta26, but not TMD0/Kir6.2, can exit the endoplastic reticulum and reach the cell membrane). Single-channel kinetic analyses revealed that the mean burst and interburst durations are shorter for TMD0/Kir6.2Delta26 than for the corresponding SUR channels. No differences were found between the two TMD0 channels. We further demonstrated that in isolation even TMD0-L0 (SUR truncated after L0) cannot confer the wild-type intrinsic gating to Kir6.2Delta26 and that swapping L0 (SUR truncated after L0)between SUR1 and SUR2A only partially exchanges their different intrinsic gating. Therefore, in addition to TMD0, L0 and the core domain also participate in determining the intrinsic gating of Kir6.2. However, TMD0 and L0 are responsible for the different gating patterns of full-length SUR1 and SUR2A channels. A kinetic model with one open and four closed states is presented to explain our results in a mechanistic context.
PubMed ID: 16887879
PMC ID: PMC1890349
Article link: J Physiol
Genes referenced: abcc8 abcc9 kcnj11