Dysfunction in Ankyrin-B Disrupts Heart Rate Regulation by Altering the Membrane Abundance of GIRK Channels.

Ankyrin-B (AnkB), encoded by ANK2, is essential for ion channel localization in the heart. We investigated its role in regulating sinoatrial node (SAN) responses to autonomic input. AnkB-haploinsufficient (AnkB+/-) mice showed baseline bradycardia, heightened SAN response to β-adrenergic stimulation, and increased heart rate variability. These mice exhibited reduced ICa,L and SAN sarcoplasmic reticulum Ca2+ content, unchanged IK,ACh density, but impaired IK,ACh desensitization. AnkB interacts with GIRK1/4 subunits, and its loss in cardiomyocyte-specific knockout mice reduced GIRK1 membrane localization. Our findings support that AnkB deficiency disrupts autonomic regulation of SAN function through downregulation of ICa,L and the reduction in IK,ACh desensitization.