Academic Journal
Selective Cell Death of Adrenocortical Cells by Pharmacological Activation of Mutant KCNJ5.
| Τίτλος: | Selective Cell Death of Adrenocortical Cells by Pharmacological Activation of Mutant KCNJ5. |
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| Συγγραφείς: | Mir-Bashiri S; Department of Medicine IV (S.M.-B., J.W., M.R., T.A.W.), Ludwig Maximilian University Hospital, Munich, Germany., Rakete S; Institute and Clinic for Occupational, Social and Environmental Medicine (S.R.), Ludwig Maximilian University Hospital, Munich, Germany., Wei J; Department of Medicine IV (S.M.-B., J.W., M.R., T.A.W.), Ludwig Maximilian University Hospital, Munich, Germany., Peitzsch M; Institute of Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany (M.P.)., Hahner S; Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital Würzburg, Germany (S.H.)., Reincke M; Department of Medicine IV (S.M.-B., J.W., M.R., T.A.W.), Ludwig Maximilian University Hospital, Munich, Germany., Williams TA; Department of Medicine IV (S.M.-B., J.W., M.R., T.A.W.), Ludwig Maximilian University Hospital, Munich, Germany. |
| Πηγή: | Hypertension (Dallas, Tex. : 1979) [Hypertension] 2026 Oct; Vol. 83 (10), pp. e27181. Date of Electronic Publication: 2026 Aug 17. |
| Τύπος έκδοσης: | Journal Article; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Lippincott, Williams & Wilkins Country of Publication: United States NLM ID: 7906255 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4563 (Electronic) Linking ISSN: 0194911X NLM ISO Abbreviation: Hypertension Subsets: MEDLINE |
| Imprint Name(s): | Publication: Original Publication: [Dallas, Tex.] : [American Heart Association], [©1979]- |
| Ιατρικοί όροι (MeSH): | G Protein-Coupled Inwardly-Rectifying Potassium Channels*/genetics , G Protein-Coupled Inwardly-Rectifying Potassium Channels*/metabolism , G Protein-Coupled Inwardly-Rectifying Potassium Channels*/agonists , Adrenal Cortex*/drug effects , Adrenal Cortex*/metabolism , Adrenal Cortex*/pathology , Adrenal Cortex*/cytology , Cell Death*/drug effects , Cell Death*/genetics , Hyperaldosteronism*/genetics , Hyperaldosteronism*/metabolism , Hyperaldosteronism*/drug therapy , Hyperaldosteronism*/pathology , Mutation*, Cell Survival/drug effects ; Membrane Potentials/drug effects ; Sodium/metabolism ; Humans |
| Περίληψη: | Background: Primary aldosteronism is frequently caused by mutations in the KCNJ5 (potassium inwardly rectifying channel subfamily J member 5) gene, encoding a G-protein inwardly rectifying potassium channel. These mutations disrupt the channel's selectivity filter, permitting abnormal sodium influx. We aimed to identify compounds that selectively activate mutant KCNJ5 channels. By further increasing sodium conductance, such compounds could induce lethal sodium influx in mutant adrenal cells, providing a targeted therapeutic strategy for primary aldosteronism caused by KCNJ5 mutations. Methods: Six small molecules identified in our prior work as potential KCNJ5 agonists were evaluated. Their effects on cell viability, sodium influx, membrane potential, and steroidogenesis were assessed in 2-dimensional and 3-dimensional human adrenocortical cells, clone 15. Results: Candidate agonists were tested for their ability to enhance adrenal cell death induced by overexpression of mutant KCNJ5. Compound 105 (C105; 2'-amino-6-chloro-1'-[2,4-difluorophenyl]-7-methyl-2,5'-dioxo-1,2,5',6',7',8'-hexahydro-1'H-spiro[indole-3,4'-quinoline]-3'-carbonitrile) increased mutant KCNJ5-induced cell death by 40% without affecting cells expressing wild-type KCNJ5. The toxic effect of C105 was abolished under low-sodium conditions. Inductively coupled plasma tandem mass spectrometry demonstrated a 25% increase in intracellular sodium after C105 treatment without significantly affecting potassium concentrations. Molecular docking indicated binding of C105 to the G-protein-binding site of KCNJ5, a key region involved in channel activation. These findings suggest that C105 promotes adrenal cell death through activation of mutant KCNJ5 and increased sodium conductance. Conclusions: C105 acts as a first-in-class mutant KCNJ5 agonist candidate and may enable pharmacological ablation of mutant cells in a subset of aldosterone-producing adenomas and familial hyperaldosteronism type III. These findings provide proof of concept for mutation-selective targeting of KCNJ5-driven primary aldosteronism. |
| Competing Interests: | S. Mir-Bashiri, M. Reincke, and T.A. Williams are inventors on the European Patent Application No. 26176673.7, filed 05.05.2026, related to “An agonist for mutant KCNJ5 channels,” assigned to Ludwig-Maximilians-Universität München, VIII.5/32/25. The other authors report no conflicts. |
| Contributed Indexing: | Keywords: adrenal cortex; aldosterone; familial hyperaldosteronism; potassium channels, inwardly rectifying; sodium |
| Substance Nomenclature: | 0 (G Protein-Coupled Inwardly-Rectifying Potassium Channels) 0 (KCNJ5 protein, human) 9NEZ333N27 (Sodium) |
| Entry Date(s): | Date Created: 20260817 Date Completed: 20260916 Latest Revision: 20261024 |
| Update Code: | 20261024 |
| DOI: | 10.1161/HYPERTENSIONAHA.126.27181 |
| PMID: | 42605674 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1524-4563 |
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| DOI: | 10.1161/HYPERTENSIONAHA.126.27181 |