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Characterization of VU0468554, a New Selective Inhibitor of Cardiac G Protein–Gated Inwardly Rectifying K+Channels
Molecular Pharmacology ( IF 3.6 ) Pub Date : 2021-12-01 , DOI: 10.1124/molpharm.121.000311
Allison Anderson 1 , Baovi N Vo 1 , Ezequiel Marron Fernandez de Velasco 1 , Corey R Hopkins 1 , C David Weaver 1 , Kevin Wickman 2
Affiliation  

G protein–gated inwardly rectifying K+ (GIRK) channels are critical mediators of excitability in the heart and brain. Enhanced GIRK-channel activity has been implicated in the pathogenesis of supraventricular arrhythmias, including atrial fibrillation. The lack of selective pharmacological tools has impeded efforts to investigate the therapeutic potential of cardiac GIRK–channel interventions in arrhythmias. Here, we characterize a recently identified GIRK-channel inhibitor, VU0468554. Using whole-cell electrophysiological approaches and primary cultures of sinoatrial nodal cells and hippocampal neurons, we show that VU0468554 more effectively inhibits the cardiac GIRK channel than the neuronal GIRK channel. Concentration-response experiments suggest that VU0468554 inhibits Gβγ-activated GIRK channels in noncompetitive and potentially uncompetitive fashion. In contrast, VU0468554 competitively inhibits GIRK-channel activation by ML297, a GIRK-channel activator containing the same chemical scaffold as VU0468554. In the isolated heart model, VU0468554 partially reversed carbachol-induced bradycardia in hearts from wild-type mice but not Girk4–/– mice. Collectively, these data suggest that VU0468554 represents a promising new pharmacological tool for targeting cardiac GIRK channels with therapeutic implications for relevant cardiac arrhythmias.

中文翻译:

VU0468554 的表征,一种新的心脏 G 蛋白选择性抑制剂——门控内向整流 K+ 通道

G 蛋白门控内向整流 K + (GIRK) 通道是心脏和大脑兴奋性的关键介质。增强的 GIRK 通道活性与室上性心律失常(包括房颤)的发病机制有关。选择性药理学工具的缺乏阻碍了研究心脏 GIRK 通道干预对心律失常的治疗潜力的努力。在这里,我们描述了最近发现的 GIRK 通道抑制剂 VU0468554。使用全细胞电生理学方法和窦房结细胞和海马神经元的原代培养,我们表明 VU0468554 比神经元 GIRK 通道更有效地抑制心脏 GIRK 通道。浓度反应实验表明 VU0468554 抑制 G βγ-以非竞争性和潜在非竞争性的方式激活 GIRK 渠道。相反,VU0468554 通过 ML297 竞争性抑制 GIRK 通道激活,ML297 是一种 GIRK 通道激活剂,含有与 VU0468554 相同的化学支架。在离体心脏模型中,VU0468554 在野生型小鼠而非Girk4 –/–小鼠的心脏中部分逆转了卡巴胆碱诱导的心动过缓。总的来说,这些数据表明 VU0468554 代表了一种有前途的新药理学工具,用于靶向心脏 GIRK 通道,对相关心律失常具有治疗意义。
更新日期:2021-11-20
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