KCNJ11 or Kir6.2 or KATP of 390 aas; 96% identical to the rat homologue, TC# 1.A.2.1.7. Congenital hyperinsulinism (CHI) is characterized by persistent insulin secretion despite severe hypoglycemia. Mutations in the pancreatic ATP-sensitive K⁺ (K(ATP)) channel proteins sulfonylurea receptor 1 (SUR1) and Kir6.2, encoded by ABCC8 and KCNJ11, respectively, is the most common cause of the disease. Many mutations in SUR1 render the channel unable to traffic to the cell surface, thereby reducing channel function. Many studies have shown that for some SUR1 trafficking mutants, the defects could be corrected by treating cells with sulfonylureas or diazoxide (Yan et al. 2007). Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium (Tammaro and Ashcroft 2007). Kir6.2 is an ATP-sensitive potassium (K_ATP) channel coupling cell metabolism to electrical activity by regulating K⁺ fluxes across the plasma membrane. Channel closure is facilitated by ATP, which binds to the pore-forming subunit (Kir6.2). Conversely, channel opening is potentiated by phosphoinositol bisphosphate (PIP₂), which binds to Kir6.2 and reduces channel inhibition by ATP.  The PIP₂ binding site has been identified (Haider et al. 2007).  KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic beta-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Martin et al. 2017 used cryo-EM to elucidate the structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea, glibenclamide, at ~6 Å resolution, revealed a closed Kir6.2 tetrameric core with four peripheral SUR1s, each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0). Intricate interactions between TMD0, the loop following TMD0, and Kir6.2 near the proposed PIP2 binding site, and where ATP density is observed, suggest that SUR1 may contribute to ATP and PIP2 binding to enhance Kir6.2 sensitivity to both. The SUR1-ABC core is found in an unusual inward-facing conformation whereby the two nucleotide binding domains are misaligned along a two-fold symmetry axis, revealing a possible mechanism by which glibenclamide inhibits channel activity (Martin et al. 2017). a cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP has been solved at 3.63 Å resolution. The structure shows that glibenclamide is lodged in the transmembrane bundle of the SUR1-ABC core connected to the first nucleotide binding domain near the inner leaflet of the lipid bilayer (Martin et al. 2017). The activation of K(ATP) channels contributes to the shortening of action potential duration but is not the primary cause of extracellular K⁺ accumulation during early myocardial ischemia (Saito et al. 2005). KATP binds nucleotides (Usher et al. 2021). Mitochondrial KATP channels stabilize intracellular Ca²⁺ during hypoxia in retinal horizontal cells of goldfish (Carassius auratus) (Country and Jonz 2021). Medicinal plant products can interact with KATP (Rajabian et al. 2022). Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal KATP channels has been observed (Flagg et al. 2004). Thus, a compensatory increase in I(Ca) counteracts a mild activation of ATP-insensitive K(ATP) channels. Pharmacological inhibitors and ATP enrich a channel conformation in which the Kir6.2 cytoplasmic domain is closely associated with the transmembrane domain, while depleting one where the Kir6.2 cytoplasmic domain is extended away into the cytoplasm. This conformational change remodels a network of intra- and inter-subunit interactions as well as the ATP and PIP2 binding pockets. The structures resolved key contacts between the distal N-terminus of Kir6.2 and SUR1's ABC module involving residues implicated in channel function and showed a SUR1 residue, K134, participates in PIP2 binding. Molecular dynamics simulations revealed two Kir6.2 residues, K39 and R54, that mediate both ATP and PIP2 binding, suggesting a mechanism for competitive gating by ATP and PIP2 (Sung et al. 2022). The natural product, 7-hydroxycoumarin (7-HC), exhibits pharmacological properties linked to antihypertensive mechanisms of action. This relaxant effect induced by 7-HC relies on K⁺-channels (K_ATP, BK_Ca, and, to a lesser extent, K_v) activation and also on Ca²⁺ influx from sarcolemma and sarcoplasmic reticulum mobilization (inositol 1,4,5-triphosphate (IP3) and ryanodine receptors) (Jesus et al. 2022). Lymphatic contractile dysfunction in mouse models of Cantú Syndrome is oberved with K_ATP channel gain-of-function mutations (Davis et al. 2023). The structure of an open K (ATP) channel has revealed tandem PIP binding sites mediating the Kir6.2 and SUR1 regulatory interface (Driggers et al. 2023).

Insulin secretion is regulated by ATP-sensitive potassium (K_ATP) channels in pancreatic β-cells. Peroxisome proliferator-activated receptors (PPAR)α ligands are used to treat dyslipidemia. A PPARα ligand, fenofibrate, and PPARγ ligands troglitazone and 15-deoxy-∆^12,14-prostaglandin J2 close K_ATP channels and induce insulin secretion. The PPARα ligand, pemafibrate, is used to treat dyslipidemia and improves glucose intolerance in mice treated with a high fat diet and a novel selective PPARα modulator, it may affect K_ATP channels or insulin secretion. The effect of fenofibrate and pemafibrate (both at 100 µM) on insulin secretion was measured. Addition of fenofibrate for 10 min increased insulin secretion in low glucose conditions. The K_ATP channel activity was measured. Although fenofibrate (100 µM) reduced the K_ATP channel current, it had no effect on insulin mRNA expression (Kitamura et al. 2023).