Caveolar Compartmentalization of Pacemaker Signaling Ensures Stable Sinoatrial Rhythmicity Which Is Disrupted in Heart Failure

BACKGROUND: Caveolae are nanoscale, plasma membrane invaginations that compartmentalize ion channels and transporters, including those involved in sinoatrial node (SAN) activity. However, role of caveolae in cardiac pacemaking remains unknown. OBJECTIVES: This study sought to determine the role of caveolae in SAN pacemaking and sinus node dysfunction (SND). METHODS: imaging, immunofluorescent and electron microscopy were performed in wild-type, cardiac-specific Cav3 knockout and 8-week post-myocardial infarction heart failure mice. Mouse and human donor SAN tissues were used for biochemical protein copurification studies. A novel 3-dimensional single SAN cell mathematical model was used to determine the impact of protein localization on SAN pacemaking. RESULTS: release event uncoupling and SND. CONCLUSIONS: SAN pacemaking is driven by complex protein interactions within a nanoscale caveolar pacemaker signalosome. Disruption of caveolae leads to SND, demonstrating a new dimension of SAN remodeling and revealing a novel therapeutic target.