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

Abstract

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. 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.

• Authors: Allison Anderson, Baovi N Vo, Ezequiel Marron Fernandez de Velasco, Corey R Hopkins, C David Weaver, Kevin Wickman
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 100 Issue 6 Pg. 540-547 (12 2021) ISSN: 1521-0111 [Electronic] United States
• PMID: 34503975 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• Potassium Channel Blockers

Topics

• Action Potentials
• Animals
• Female
• G Protein-Coupled Inwardly-Rectifying Potassium Channels (antagonists & inhibitors, metabolism)
• HEK293 Cells
• Hippocampus (cytology, metabolism, physiology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (drug effects, metabolism, physiology)
• Neurons (drug effects, metabolism, physiology)
• Potassium Channel Blockers (pharmacology)