ArticleHuman genetics2009
KATP channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response.
Article in Human genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 35 citations in OpenAlex.
- KArhiv za farmaciju · 2024Article
- Associations of ATP-Sensitive Potassium Channel's Gene Polymorphisms With Type 2 Diabetes and Related Cardiovascular Phenotypes.Frontiers in cardiovascular medicine · 2022Article
- The Pharmacology of ATP-Sensitive KHandbook of experimental pharmacology · 2021Article
- Ischemic Heart Disease and Heart Failure: Role of Coronary Ion Channels.International journal of molecular sciences · 2020Review
- Genetic Discovery of ATP-Sensitive KCirculation. Arrhythmia and electrophysiology · 2019Review
- Article
- DNA methylation of candidate genes in peripheral blood from patients with type 2 diabetes or the metabolic syndrome.PloS one · 2017Article
- Plasticity of sarcolemmal KATP channel surface expression: relevance during ischemia and ischemic preconditioning.American journal of physiology. Heart and circulatory physiology · 2016Article
- KATP Channels in the Cardiovascular System.Physiological reviews · 2016Review
- Cardiovascular KPathobiology of aging & age related diseases · 2016Review
- Association Between KCNJ11 Gene E23K Polymorphism and Body Composition Together with its Response to Endurance Training.The open biomedical engineering journal · 2015Article
- The role of ATP-sensitive potassium channels in cellular function and protection in the cardiovascular system.British journal of pharmacology · 2014Review
- Spot14/Mig12 heterocomplex sequesters polymerization and restrains catalytic function of human acetyl-CoA carboxylase 2.Journal of molecular recognition : JMR · 2013Article
- The molecular genetics of sulfonylurea receptors in the pathogenesis and treatment of insulin secretory disorders and type 2 diabetes.Current diabetes reports · 2011Review
- Advances in cardiac ATP-sensitive K+ channelopathies from molecules to populations.Circulation. Arrhythmia and electrophysiology · 2011Article
- K(ATP) channel-dependent metaboproteome decoded: systems approaches to heart failure prediction, diagnosis, and therapy.Cardiovascular research · 2011Review
- K(ATP) channels process nucleotide signals in muscle thermogenic response.Critical reviews in biochemistry and molecular biology · 2010Article
- ATP-sensitive K(+) channel-deficient dilated cardiomyopathy proteome remodeled by embryonic stem cell therapy.Stem cells (Dayton, Ohio) · 2010Article
- Human K(ATP) channelopathies: diseases of metabolic homeostasis.Pflugers Archiv : European journal of physiology · 2010Review
- Quaternary structure of KATP channel SUR2A nucleotide binding domains resolved by synchrotron radiation X-ray scattering.Journal of structural biology · 2010Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
ATP-sensitive K+ (K(ATP)) channels maintain cardiac homeostasis under stress, as revealed by murine gene knockout models of the KCNJ11-encoded Kir6.2 pore. However, the translational significance of K(ATP) channels in human cardiac physiology remains largely unknown. Here, the frequency of the minor K23 allele of the common functional Kir6.2 E23K polymorphism was found overrepresented in 115 subjects with congestive heart failure compared to 2,031 community-based controls (69 vs. 56%, P < 0.001). Moreover, the KK genotype, present in 18% of heart failure patients, was associated with abnormal cardiopulmonary exercise stress testing. In spite of similar baseline heart rates at rest among genotypic subgroups (EE: 72.2 ± 2.3, EK: 75.0 ± 1.8 and KK:77.1 ± 3.0 bpm), subjects with the KK genotype had a significantly reduced heart rate increase at matched workload (EE: 32.8 ± 2.7%, EK: 28.8 ± 2.1%, KK: 21.7 ± 2.6%, P < 0.05), at 75% of maximum oxygen consumption (EE: 53.9 ± 3.9%, EK: 49.9 ± 3.1%, KK: 36.8 ± 5.3%, P < 0.05), and at peak V(O2) (EE: 82.8 ± 6.0%, EK: 80.5 ± 4.7%, KK: 59.7 ± 8.1%, P < 0.05). Molecular modeling of the tetrameric Kir6.2 pore structure revealed the E23 residue within the functionally relevant intracellular slide helix region. Substitution of the wild-type E residue with an oppositely charged, bulkier K residue would potentially result in a significant structural rearrangement and disrupted interactions with neighboring Kir6.2 subunits, providing a basis for altered high-fidelity K(ATP) channel gating, particularly in the homozygous state. Blunted heart rate response during exercise is a risk factor for mortality in patients with heart failure, establishing the clinical relevance of Kir6.2 E23K as a biomarker for impaired stress performance and underscoring the essential role of K(ATP) channels in human cardiac physiology.
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