3.A.1.208.23
The Sur2B (ABCC9) sulfonylurea receptor. The amino-terminal transmembrane domain of Sur2B binds Kir6.2 (Winkler et al., 2011). Dominant missense mutations in ABCC9, promoting open channel formation, cause Cantú syndrome (Harakalova et al., 2012; van Bon et al., 2012). This protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity.  Associated with early repolarization (ERS) and Brugada (BrS) syndromes (Hu et al. 2014).  This ATP-sensitive potassium (K(ATP)) channel couples glucose metabolism to insulin secretion in pancreatic beta-cells (de Wet et al. 2007). The vasodilator binding sites on the SUR2 subunit have been identified (Ding et al. 2022). Cryo-EM structures of SUR2A and SUR2B subunits in complex with Mg-nucleotides and P1075 or levcromakalim, two chemically distinct KATP openers that are specific to SUR2, have been determined. Both P1075 and levcromakalim bind to a common site in the transmembrane domain (TMD) of the SUR2 subunit, which is between TMD1 and TMD2 and is embraced by TMSs 10, 11, 12, 14, and 17. These KATP openers synergize with Mg-nucleotides to stabilize SUR2 in the NBD-dimerized occluded state to activate the channel (Ding et al. 2022). A novel ABCC9 variant in a family with Cantu syndrome affecting multiple generations highlights the functional role of the SUR2B NBD1(Gao et al. 2024).  Cantu syndrome (CS) (OMIM #239850) is an autosomal dominant multiorgan system condition, associated with a characteristic facial phenotype, hypertrichosis, and multiple cardiovascular complications. CS is caused by gain-of-function (GOF) variants in KCNJ8 or ABCC9 that encode pore-forming Kir6.1 and regulatory SUR2 subunits of ATP-sensitive potassium (K_ATP) channels. A novel heterozygous ABCC9 variant, c.2440G>T; p.Gly814Trp, was identified in three individuals from a four generation Greek family. The membrane potential in cells stably expressing hKir6.1 and hSUR2B with p.Gly814Trp was hyperpolarized compared to cells expressing WT channels, and inside-out patch-clamp assays of K_ATP channels formed with hSUR2B p.Gly814Trp demonstrated a decreased sensitivity to ATP inhibition, confirming a relatively mild GOF effect of this variant. The specific location of the variant reveals an unrecognized functional role of the first glycine in the signature motif of the nucleotide binding domains in ATP-binding cassette (ABC) protein ion channels (Gao et al. 2024).