Disease relevance of Kcnj11

• Mice with dominant-negative reduction of beta cell K(ATP) (Kir6.2[AAA]) exhibit hyperinsulinism, whereas mice with zero K(ATP) (Kir6.2(-/-)) show transient hyperinsulinaemia as neonates, but are glucose-intolerant as adults [1].
• Mutant mice lacking the Kir6.2 subunit of K(ATP) channels [knockout (KO) mice] were susceptible to generalized seizures after brief hypoxia [2].
• Although pancreatic alpha-cells were functional in Kir6.2-/-, the mice exhibited a severe defect in glucagon secretion in response to systemic hypoglycemia [3].
• The glucose-lowering effect of insulin, as assessed by an insulin tolerance test, is increased significantly in Kir6.2(-/-), which could protect Kir6.2(-/-) from developing hyperglycemia [4].
• In the absence of Kir6.2, vigorous sympathetic challenge caused arrhythmia and sudden death, preventable by calcium-channel blockade [5].

Psychiatry related information on Kcnj11

• The mild glucose intolerance that is observed in the Kir6.2 knockout mice is unlikely to have created the memory deficits observed [6].
• Thus, our results suggest that loss of Kir6.2-containing K(ATP) channels does affect animal behavior under metabolic control conditions, especially in novel situations [7].
• As a comprehensive behavioral description of Kir6.2 KO mice under physiological control conditions has not yet been carried out, we subjected Kir6.2 KO and corresponding wild-type (WT) mice to a test battery to assess emotional behavior, motor activity and coordination, species-typical behaviors and cognition [7].

High impact information on Kcnj11

• Genetic inactivation of the K-ATP channel pore-forming subunit Kir6.2 resulted in a selective rescue of SN but not VTA DA neurons in two mechanistically distinct mouse models of dopaminergic degeneration, the neurotoxicological 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model and the mutant weaver mouse [8].
• Kir6.2 is the pore-forming subunit of K(ATP) channels in many cell types, including pancreatic beta-cells and heart [3].
• Here we show the complete absence of both functional ATP-sensitive K+ (K(ATP)) channels and glucose responsiveness in the neurons of the ventromedial hypothalamus (VMH) in Kir6.2-/- mice [3].
• The structure, in combination with molecular modelling, suggests how SUR1 interacts with Kir6.2 [9].
• A molecular model of the C-terminus of Kir6.2 (based on the crystal structure of Kir3.1) was constructed and automated docking was used to identify residues interacting with ATP [10].

Biological context of Kcnj11

• MATERIALS AND METHODS: Heterozygous Kir6.2(+/-) and SUR1(+/-) animals were generated by backcrossing from knockout animals [1].
• CONCLUSIONS/INTERPRETATION: A significant proportion of Kir6.2 and SUR1 subunits reside on insulin-secretory vesicles and the distal secretory pathway in mouse beta cells but do not influence intravesicular ion homeostasis [11].
• Identification of residues contributing to the ATP binding site of Kir6.2 [10].
• Using cysteine-scanning mutagenesis and charged thiol-modifying reagents, we identified two amino acids in Kir6.2 that appear to interact directly with ATP: R50 in the N-terminus, and K185 in the C-terminus [10].
• Here, upon catecholamine challenge, disruption of KATP channels, by genetic deletion of the pore-forming Kir6.2 subunit, produced defective cardiac action potential shortening, predisposing the myocardium to early afterdepolarizations [12].

Anatomical context of Kcnj11

• We co-expressed Kir6.2 with wild-type or mutant SUR in Xenopus oocytes and recorded the resulting currents in inside-out macropatches [13].
• RESULTS: SUR1 and Kir6.2 immunoreactivity were concentrated on dense-core vesicles and on vesicles plus the endoplasmic reticulum/Golgi network, respectively, in both islets and MIN6 cells [11].
• The basal 2-deoxyglucose uptake rate in skeletal muscle of double-knockout mice is increased similarly to the rate in Kir6.2 knockout mice [14].
• An oral glucose tolerance test, insulin tolerance test and batch incubation study of pancreatic islets were performed on double-knockout mice and Kir6.2-knockout mice [15].
• These results suggest a compensatory higher GLUT4 inclusion at the cellular neuronal membrane in the cerebral cortex, hippocampus and cerebellum of the Kir6.2(-/-) K-ATP knockout mice [6].

Associations of Kcnj11 with chemical compounds

• In contrast, pretreatment with glucagon-like peptide-1 (GLP-1) in Kir6.2(-/-) mice potentiated insulin secretion and blunted the rise in blood glucose levels [16].
• We have generated transgenic mice expressing a dominant-negative form of the KATP channel subunit Kir6.2 (Kir6.2G132S, substitution of glycine with serine at position 132) in pancreatic beta cells [17].
• Formed through association of the Kir6.2 pore and the sulfonylurea receptor, the stress-responsive ATP-sensitive K(+) channels (K(ATP) channels), with their metabolic-sensing capability and broad tissue expression, are potential candidates for integrating the systemic adaptive response to repetitive exercise [18].
• The novel diazoxide analog 3-isopropylamino-7-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide is a selective Kir6.2/SUR1 channel opener [19].
• We additionally demonstrated that pyruvate kinase also interacts with Kir6.2 subunits [20].

Regulatory relationships of Kcnj11

• Here we show evidence for the interaction of H+ with ATP in regulating a cloned K(ATP) channel, i.e. Kir6.2 expressed with and without the SUR1 subunit [21].
• Kir6.2-deficient mice are susceptible to stimulated ANP secretion: K(ATP) channel acts as a negative feedback mechanism [22]?
• To examine the role of sarcolemmal K(ATP) channels in cardiac function, we generated transgenic mice expressing GFP-tagged Kir6.2 subunits with reduced ATP sensitivity under control of the cardiac alpha-myosin heavy chain promoter [23].

Other interactions of Kcnj11

• In contrast to wild-type, surviving dopaminergic SN neurons of homozygous weaver mouse exclusively expressed SUR1 + Kir6.2 during the active period of dopaminergic neurodegeneration [24].
• In mice lacking K(ATP) channels (Kir6.2(-/-) mice), we found that pretreatment with GIP in vivo failed to blunt the rise in blood glucose levels after oral glucose load [16].
• Accordingly, disruption of the IRS-1 gene affects neither systemic insulin sensitivity nor glucose uptake in skeletal muscles of Kir6.2-deficient mice [14].
• METHODS: Double-knockout mice were generated by intercrossing Kir6.2-knockout mice with GIP receptor-knockout mice [15].
• Kir6.2-SUR2A currents exhibited a single low-affinity site with a Ki of 0.8 +/- 0.1 mmol/l (n = 5), which is likely to reside on the Kir6.2 subunit [25].

Analytical, diagnostic and therapeutic context of Kcnj11

• Perfusion experiments of Kir6.2(-/-) mice revealed severely impaired potentiation of insulin secretion by 1 nmol/l GIP and substantial potentiation by 1 nmol/l GLP-1 [16].
• Relative to their corresponding wild type, semi-quantitative immunohistochemistry showed that GLUT4 protein expression as measured by a GLUT4 antibody recognizing an extracellular epitope was increased in the Kir6.2(-/-) K-ATP mice [6].
• Here, we report the heterologous expression and purification of a functionally active K(ATP) channel complex composed of pore-forming Kir6.2 and regulatory SUR1 subunits, and determination of its structure at 18 A resolution by single-particle electron microscopy [9].
• The sites of Kir6.2 mRNA expression were determined by in situ hybridization histochemistry with a digoxigenin (DIG)-labeled antisense cRNA probe [26].
• In situ hybridization and immunofluorescence staining of serial sections with the anti-insulin, the anti-glucagon, and the anti-somatostatin antibodies showed Kir6.2 mRNA to be present in alpha-, beta-, and delta-cells [26].

References