A functional role of the C-terminal 42 amino acids of SUR2A and SUR2B in the physiology and pharmacology of cardiovascular ATP-sensitive K+ channels

The ATP-sensitive K+ (KATP) channel is composed of four pore-forming Kir6.2 subunits and four sulfonylurea receptors (SUR). Intracellular ATP inhibits KATP channels through Kir6.2. SUR is an ABC protein bearing transmembrane domains and two nucleotide-binding domains (NBD1 and NBD2). SUR increases the open probability of KATP channels by interacting with ATP and ADP through NBDs and with K+ channel openers such as nicorandil through its transmembrane domain. Because NBDs and the drug receptor allosterically interact with each other, nucleotides and drugs probably activate KATP channels by causing the same conformational change of SUR. SUR2A and SUR2B have the identical drug receptor and NBDs and differ only in the C-terminal 42 amino acids (C42). Nonetheless, nicorandil ~100 times more potently activates SUR2B/Kir6.2 than SUR2A/Kir6.2 channels. Based on our allosteric model, we have analyzed the interaction between NBDs and the drug receptor in SUR2A and SUR2B and found that both nucleotide-bound NBD1 and NBD2 more strongly induce the conformational change in SUR2B than SUR2A. Therefore, C42 modulates the function of not only NBD2 which is close to C42 in a primary structure but NBD1 which is more than 630 amino acid N-terminal to C42. This raises the possibility that in the presence of nucleotides, NBD1 and NBD2 dimerize to induce the conformational change and that the dimerization enables C42 to gain access to both NBDs. Modulation of the nucleotide-NBD1 and -NBD2 interactions by C42 would determine the stability of the nucleotide-dependent dimer and thus, the physiological and pharmacological properties of KATP channels.