Desmosomal junctions are necessary for adult sinus node function

Area of Science:

• Cardiovascular Biology
• Cellular Cardiology
• Molecular Mechanisms of Cardiac Function

Background:

• Cardiac pacemaker function traditionally focuses on ion and gap junction channels.
• Pacemaker cells possess desmosomes, cell adhesion structures, whose role in pacemaker activity is unexplored.

Purpose of the Study:

• To investigate the role of desmosomes in cardiac pacemaker function.
• To elucidate the contribution of desmoplakin (DSP), a key desmosomal protein, to sinoatrial node (SAN) activity.

Main Methods:

• Generated a cardiac conduction-specific desmoplakin knockout (csKO) mouse model (Hcn4-Cre-ERT2; DSP f/f).
• Analyzed adult DSP csKO mice and a patient with a pathogenic DSP variant.
• Utilized in vivo, ex vivo (intact atria), and in vitro (cardiomyocytes) approaches.

Main Results:

• Desmosomal dysregulation, specifically DSP loss, caused increased sinus pauses and sinus node dysfunction without cardiomyopathy.
• DSP csKO mice exhibited impaired beat-to-beat regulation and migrating pacemaker sites linked to connexin 45 loss.
• In vitro studies confirmed DSP loss impacts beat-to-beat regulation in cardiomyocytes.

Conclusions:

• Desmosomes play an essential, previously unrecognized role in cardiac pacemaker function.
• This finding provides a novel mechanism for understanding beat-to-beat regulation and sinus node diseases.
• Highlights the importance of desmosomal integrity for maintaining normal heart rhythm.