4.5 Article

Characterization of VU0468554, a New Selective Inhibitor of Cardiac G Protein-Gated Inwardly Rectifying K+ Channels

期刊

MOLECULAR PHARMACOLOGY
卷 100, 期 6, 页码 540-547

出版社

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/molpharm.121.000311

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资金

  1. National Institutes of Health (NIH) National Heart, Lung, and Blood Institute [RO1 HL105550]
  2. National Institute on Drug Abuse [R01 DA034696]
  3. National Institute on Alcohol Abuse and Alcoholism [R01 AA027544]
  4. NIH National Heart, Lung, and Blood Institute [F31 HL139090]
  5. NIH National Institute of Mental Health [R01 MH107399]

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The newly identified GIRK channel inhibitor VU0468554 shows effective inhibition of cardiac GIRK channels, indicating promising therapeutic implications for relevant cardiac arrhythmias. Studies suggest that VU0468554 selectively targets cardiac over neuronal GIRK channels and partially reverses GIRK-mediated bradycardia in isolated mouse heart models.
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 supra ventricular 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 G beta gamma-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. SIGNIFICANCE STATEMENT Although cardiac GIRK-channel inhibition shows promise for the treatment of supraventricular arrhythmias, the absence of subtype-selective channel inhibitors has hindered exploration into this therapeutic strategy. This study utilizes whole-cell patch-clamp electrophysiology to characterize the new GIRK-channel inhibitor VU0468554 in human embryonic kidney 293T cells and primary cultures. We report that VU0468554 exhibits a favorable pharmacodynamic profile for cardiac over neuronal GIRK channels and partially reverses GIRK-mediated bradycardia in the isolated mouse heart model.

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