ArticleACS chemical biology2011
Selective inhibition of the K(ir)2 family of inward rectifier potassium channels by a small molecule probe: the discovery, SAR, and pharmacological characterization of ML133.
Article in ACS chemical biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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66 citing papers in PubMed, 97 citations in OpenAlex.
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- KCNJ2 is Required for NLRP3 Inflammasome Activation That Drives Allergic Airway Inflammation and Remodeling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Characterization of Next-Generation Inhibitors for the Inward-Rectifier Potassium Channel KACS medicinal chemistry letters · 2025Article
- High-yield production and characterization of functional Kir2.1 ion channel usingSynthetic and systems biotechnology · 2025Article
- Decoding Potassium Homeostasis in Cancer Metastasis and Drug Resistance: Insights from a Highly Selective DNAzyme-Based Intracellular KJournal of the American Chemical Society · 2025Article
- Heterogeneity in oligodendrocyte precursor cell proliferation is dynamic and driven by passive bioelectrical properties.Cell reports · 2024Article
- Impairment of microvascular endothelial Kir2.1 channels contributes to endothelial dysfunction in human hypertension.American journal of physiology. Heart and circulatory physiology · 2024Article
- The network of cardiac KNaunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Ionic mechanisms involved in arginine vasopressin-mediated excitation of auditory cortical and thalamic neurons.Molecular and cellular neurosciences · 2024Article
- Leptin excites basolateral amygdala principal neurons and reduces food intake by LepRb-JAK2-PI3K-dependent depression of GIRK channels.Journal of cellular physiology · 2024Article
- Neuromedin B excites central lateral amygdala neurons and reduces cardiovascular output and fear-potentiated startle.Journal of cellular physiology · 2023Article
- Article
- Ionic signalling mechanisms involved in neurokinin-3 receptor-mediated augmentation of fear-potentiated startle response in the basolateral amygdala.The Journal of physiology · 2022Article
- Kir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters.Nature communications · 2022Article
- VU6036720: The First Potent and Selective In Vitro Inhibitor of Heteromeric Kir4.1/5.1 Inward Rectifier Potassium Channels.Molecular pharmacology · 2022Article
- Alzheimer's disease and cerebrovascular pathology alter inward rectifier potassium (KBritish journal of pharmacology · 2022Article
- Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas.Signal transduction and targeted therapy · 2022Article
- KPhysiological reports · 2022Article
6 more citing papers are in PubMed but not listed here.
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13 authors at 4 institutions in 1 country.
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Abstract
The K(ir) inward rectifying potassium channels have a broad tissue distribution and are implicated in a variety of functional roles. At least seven classes (K(ir)1-K(ir)7) of structurally related inward rectifier potassium channels are known, and there are no selective small molecule tools to study their function. In an effort to develop selective K(ir)2.1 inhibitors, we performed a high-throughput screen (HTS) of more than 300,000 small molecules within the MLPCN for modulators of K(ir)2.1 function. Here we report one potent K(ir)2.1 inhibitor, ML133, which inhibits K(ir)2.1 with an IC(50) of 1.8 μM at pH 7.4 and 290 nM at pH 8.5 but exhibits little selectivity against other members of Kir2.x family channels. However, ML133 has no effect on K(ir)1.1 (IC(50) > 300 μM) and displays weak activity for K(ir)4.1 (76 μM) and K(ir)7.1 (33 μM), making ML133 the most selective small molecule inhibitor of the K(ir) family reported to date. Because of the high homology within the K(ir)2 family-the channels share a common design of a pore region flanked by two transmembrane domains-identification of site(s) critical for isoform specificity would be an important basis for future development of more specific and potent K(ir) inhibitors. Using chimeric channels between K(ir)2.1 and K(ir)1.1 and site-directed mutagenesis, we have identified D172 and I176 within M2 segment of K(ir)2.1 as molecular determinants critical for the potency of ML133 mediated inhibition. Double mutation of the corresponding residues of K(ir)1.1 to those of K(ir)2.1 (N171D and C175I) transplants ML133 inhibition to K(ir)1.1. Together, the combination of a potent, K(ir)2 family selective inhibitor and identification of molecular determinants for the specificity provides both a tool and a model system to enable further mechanistic studies of modulation of K(ir)2 inward rectifier potassium channels.
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