HCN channels in the heart

Wu, Yakun (2025): HCN channels in the heart: prevalence and rhythmic function. Dissertation, LMU München: Faculty of Chemistry and Pharmacy

Abstract

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in cardiac pacemaking and rate modulation. This project investigated the expression and functional remodeling of HCN isoforms, particularly HCN1, in the healthy and hypertrophic mouse heart. Under hypertrophic conditions, HCN1 expression is upregulated in the ventricles, suggesting disease-associated remodeling beyond the conduction system. This spatial distribution reflects distinct functional roles of HCN channels, essential for pacemaking and potentially implicated in arrhythmogenesis. In this study, we also determined phase response curves (PRCs) in mouse sinoatrial pacemaker cells to investigate network synchronization. PRC analysis revealed impaired phase entrainment in HCN1 knockout (HCN1KO) cells, where HCN1 contributes more to phase advance than to phase delay. In addition, our cAMP insensitive HCN1 mouse model (HCN1EA) further suggest that the cyclic nucleotide-binding domain (CDR) of HCN1 is crucial for the chronotropic effect and heart rate stabilization. These findings advance our understanding of HCN channel remodeling in cardiac disease and their contributions to heart rate regulation.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: HCN channels, heart rhythm, pacemaker cells, SAN
• Subjects: 500 Natural sciences and mathematics; 500 Natural sciences and mathematics > 540 Chemistry and allied sciences
• Faculties: Faculty of Chemistry and Pharmacy
• Language: English
• Date of oral examination: 8. April 2025
• 1. Referee: Biel, Martin
• Signature of the printed copy: 0001/UMC 31954