Journal Article Epublish
PubMed: 42780784 DOI: 10.3389/fphar.2026.1899932
Selective inhibition of LY294002 across cloned human cardiac ion channels: implications for atrium-selective therapy in atrial fibrillation.
Front Pharmacol 17:1899932
Authors: Rui Niu, Jiawei Li, Huanle Fang, Wei Zhao, Chao Dong, Ningjuan Han, Mengyuan Chen, Lie Ma, Liang Li, Yun Fan, Bing Zhu, Beibei Bie, Jie Wu, Hiroshi Matsuura, Minoru Horie
Affiliations
- Medical School of Xi'an Peihua University, Xi'an, Shaanxi, China.
- Medical School of Xi'an Peihua University, Xi'an, Shaanxi, China. Guangdong-Hong Kong-Macao Greater Bay Area Center for Drug Evaluation and Inspection, National Medical Products Administration, Shenzhen, Guangdong Province, China.
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Medical University, Xi'an, China.
- Medical School of Xi'an Peihua University, Xi'an, Shaanxi, China. Innovation Laboratory for Natural Medicine Research and Translation, Xi'an Peihua University, Xi'an, China.
- Medical School of Xi'an Peihua University, Xi'an, Shaanxi, China. Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, Japan. Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
- Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, Japan.
- Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Abstract
BACKGROUND AND PURPOSE
Atrial fibrillation (AF) is the most prevalent clinical arrhythmia, yet current antiarrhythmic pharmacotherapies have limited efficacy and pose risks of off-target ventricular block. LY294002 was reported to inhibit the ultrarapid delayed-rectifier potassium current (I Kur) carried by Kv1.5 channels, a promising atrium-selective therapeutic target for AF. To determine whether LY294002 exhibits functional selectivity for I Kur, this study comprehensively examined its inhibitory effects on major counter-target cardiac ion currents.
METHODS
The cDNAs encoding the principal pore-forming subunits of major cardiac channels-mediating I Kr(Kv11.1), I Ks(Kv7.1), I K1(Kir2.1), I to(Kv4.3), I Na(Nav1.5), and I Ca-L(Cav1.2)-were heterologously expressed in Chinese hamster ovary cells. The inhibitory effects of LY294002 on these channels were assessed using the whole-cell patch-clamp technique. Furthermore, molecular docking analysis was conducted to characterize the structural interactions and binding configurations of LY294002 with Kv1.5.
RESULTS
LY294002 inhibited all investigated currents in a concentration-dependent manner, albeit with markedly varying potencies. Based on Hill equation fits, the half-maximal inhibitory concentration (IC 50) values for LY294002 on I Ks, I Kr , I to , I K1, I Na, and I Ca-L were 21.5, 26.3, 55.9, 81.5, 131.6, and 46.5 μM, respectively. Notably, the lowest off-target IC 50 (I Ks) was approximately 2.7-fold higher than the previously reported IC 50 for I Kur (7.9 μM). Molecular docking analysis revealed that LY294002 bound within the internal cavity of Kv1.5, with predicted binding affinity of -8.3 kcalImol -1.
CONCLUSION
The inhibitory potency of LY294002 against I Kur is substantially higher than its potency against other major cardiac currents, demonstrating its potential to act as a selective I Kur blocker. Structurally, this preferential inhibition is likely mediated by the compound's favorable occupancy of key gating or pore regions unique to the Kv1.5 channel conformation.
MeSH
Cells, Atrial Fibrillation, Ion Channels, Therapeutics