3.A.1.208.4
SUR1 sulfonylurea receptor; subunit and regulator of α-cell ATP-sensitive K⁺ channel (TC #1.A.2); determines ATP sensitivity; no inherent transport function known; associated with persistent hyperinsulinemic hypoglycemia of infancy due to focal adenomatous hyperplasia (also called ABCC8). Gain-of-function mutations in the genes encoding the ATP-sensitive potassium (K(ATP)) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) cause neonatal diabetes mellitus. Because mutant channels are inhibited less strongly by MgATP, this increases K(ATP) currents in pancreatic beta cells, thus reducing insulin secretion and producing diabetes (de Wet et al., 2007). Binds ligands (blockers): glibenclamide, tolbutamide, and meglitinide as well as agonists, SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide (Bessadok et al., 2011). ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 and Kir6.2 with diminished PIP2 sensitivity (Pratt and Shyng, 2011). Dominant missense mutations in ABCC9, promoting open channel formation, cause Cantú syndrome (Harakalova et al., 2012; van Bon et al., 2012). The N-terminal transmembrane domain of SUR1 controls gating of Kir6.2 by modulating channel sensitivity to PIP2 (Pratt et al., 2011). Familial mild hyperglycemia is due to the ABCC8-V84I mutation (Gonsorcikova et al., 2011). ATP regulates KATP channels by promoting dimerization and conformational switching (Ortiz et al. 2013).  Mutations causing neonatal diabetes are attributed to alterations in the affinites for ATP and ADP (Ortiz and Bryan 2015).  Two groups of mutations with different cellular mechanisms have been identified. 1) Channel complexes with mutations in NBD2 of SUR1 traffic normally but are unable to be activated by MgADP. 2) Channel mutations in the TMS domains of SUR1 are retained in the ER and have variable functional impairment (Nessa et al. 2015). KATP channels (Kir6.2/SUR1) in the brain and endocrine pancreas  couple metabolic status to the membrane potential. In beta-cells, increases in cytosolic [ATP/ADP] inhibit KATP channel activity, leading to membrane depolarization and exocytosis of insulin granules. Mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) can result in gain or loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI), respectively.  Nucleotide binding without hydrolysis switches SUR1 to stimulatory conformations.  Increased affinity for ATP gives rise to ND while decreased affinty gives rise to CHI (Ortiz and Bryan 2015). SUR1 mutations constitute a genetic aetiology for neonatal diabetes, and they act by reducing the K_ATP channel's ATP sensitivity (Proks et al. 2006). Polymorphic ABCC8 isoforms are key regulatory proteins of cerebral oedema in many neurological disorders including traumatic brain injury (Jha et al. 2018). In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk while different variant polymorphisms are associated with favourable outcome, potentially suggesting distinct mechanisms (Jha et al. 2018). KATP channels are energy sensors that are clinically validated drug targets. KATP inhibitors are prescribed for diabetes and KATP activators are used for the treatment of hypoglycemia, hypertension, and hair loss. Wu et al., 2022 [PMID 36253099] highlight the current knowledge about the drug binding modes observed using cryogenic EM. The inhibitors and activators bind to two distinct sites in the transmembrane domain of the SUR subunit. These drugs allosterically modulate the dimerization of SUR nucleotide-binding domains (NBDs) and thus KATP channel activity (Wu et al., 2022 [PMID 36253099]).