Characterization of VU0468554, a new selective inhibitor of cardiac G protein–gated inwardly rectifying K1 channels

Allison Anderson, Baovi Vo, Ezequiel Marron Fernandez de Velasco, Corey R. Hopkins, C. David Weaver, Kevin Wickman

Research output: Contribution to journalArticlepeer-review


G protein–gated inwardly rectifying K1 (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 Gbc-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.

Original languageEnglish (US)
Pages (from-to)540-547
Number of pages8
JournalMolecular Pharmacology
Issue number6
StatePublished - Dec 1 2021

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) National Heart, Lung, and Blood Institute [Grant RO1 HL105550], National Institute on Drug Abuse [Grant R01 DA034696], and National Institute on Alcohol Abuse and Alcoholism [Grant R01 AA027544] (to K.W.); NIH National Heart, Lung, and Blood Institute [Grant F31 HL139090] (to A.A.); and NIH National Institute of Mental Health [Grant R01 MH107399] (to K.W., C.R.H., and C.D.W.). The authors declare no conflicts of interest.

Publisher Copyright:
Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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