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

Abstract

G protein-gated inwardly rectifying K + (GIRK/Kir3) 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 G-activated GIRK channels in non-competitive, 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.

Relevance of KCNJ5 in Pathologies of Heart Disease

“…Notable compounds include VU0458554 and benzopyran-G1. VU0468554 is an inhibitor that displayed selectivity for cardiac GIRK1/GIRK4 tetramers, while benzopyran-G1 is an inhibitor that targets GIRK1-containing channels, including K ACh [ 81 , 82 ]. An additional inhibitor selective for K ACh , XAF-1407, effectively terminated arrhythmic phenotypes in equine and goat models of AF [ 83 , 84 ].…”