Desmosomal junctions are necessary for adult sinus node function.
Current mechanisms driving cardiac pacemaker function have focused on ion channel and gap junction channel function, which are essential for action potential generation and propagation between pacemaker cells. However, pacemaker cells also harbour desmosomes that structurally anchor pacemaker cells to each other in tissue, but their role in pacemaker function remains unknown.



To determine the role of desmosomes in pacemaker function, we generated a novel mouse model harbouring cardiac conduction-specific ablation (csKO) of the central desmosomal protein, desmoplakin (DSP) using the Hcn4-Cre-ERT2 mouse line. Hcn4-Cre targets cells of the adult mouse sinoatrial node (SAN) and can ablate DSP expression in the adult DSP csKO SAN resulting in specific loss of desmosomal proteins and structures. Dysregulation of DSP via loss-of-function (adult DSP csKO mice) and mutation (clinical case of a patient harbouring a pathogenic DSP variant) in mice and man, respectively, revealed that desmosomal dysregulation is associated with a primary phenotype of increased sinus pauses/dysfunction in the absence of cardiomyopathy. Underlying defects in beat-to-beat regulation were also observed in DSP csKO mice in vivo and intact atria ex vivo. DSP csKO SAN exhibited migrating lead pacemaker sites associated with connexin 45 loss. In vitro studies exploiting ventricular cardiomyocytes that harbour DSP loss and concurrent early connexin loss phenocopied the loss of beat-to-beat regulation observed in DSP csKO mice and atria, extending the importance of DSP-associated mechanisms in driving beat-to-beat regulation of working cardiomyocytes.



We provide evidence of a mechanism that implicates an essential role for desmosomes in cardiac pacemaker function, which has broad implications in better understanding mechanisms underlying beat-to-beat regulation as well as sinus node disease and dysfunction.
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613C, USA.
Valeria
V
Mezzano
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613C, USA.
Yan
Y
Liang
Department of Bioengineering, University of California-San Diego, La Jolla, CA 92093, USA.
Adam T
AT
Wright
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613C, USA.
Robert C
RC
Lyon
Department of Bioengineering, University of California-San Diego, La Jolla, CA 92093, USA.
Emily
E
Pfeiffer
Scripps Translational Science Institute, Department of Medicine, Scripps Green Hospital, La Jolla, CA 92037, USA.
Michael Y
MY
Song
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613C, USA.
Yusu
Y
Gu
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613C, USA.
Nancy D
ND
Dalton
Department of Cardiac Electrophysiology, University of California-San Francisco, San Francisco, CA 94143, USA.
Melvin
M
Scheinman
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613C, USA.
Kirk L
KL
Peterson
Skaggs School of Pharmacy, University of California-San Diego, La Jolla, CA 92093, USA.
Sylvia M
SM
Evans
Cardiovascular Genetics Program, New York University School of Medicine, New York, NY 10016, USA.
Steven
S
Fowler
Cardiovascular Genetics Program, New York University School of Medicine, New York, NY 10016, USA.
Marina
M
Cerrone
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613C, USA Department of Bioengineering, University of California-San Diego, La Jolla, CA 92093, USA.
Andrew D
AD
McCulloch
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613C, USA fasheikh@ucsd.edu.
Farah
F
Sheikh
D000200:Action Potentials; D000367:Age Factors; D000818:Animals; D016275:Atrial Function; D001683:Biological Clocks; D002478:Cells, Cultured; D017630:Connexins / Q000378:metabolism; D051180:Desmoplakins / Q000172:deficiency / Q000235:genetics; D003896:Desmosomes / Q000378:metabolism / Q000648:ultrastructure; D020022:Genetic Predisposition to Disease; D006339:Heart Rate; D006801:Humans; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D012804:Sick Sinus Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012849:Sinoatrial Node / Q000378:metabolism / Q000503:physiopathology* / Q000648:ultrastructure; D013997:Time Factors
D017630:Connexins; D051180:Desmoplakins; C082920:connexin 45
Arrhythmia (mechanisms); Desmosome; Heart rate variability; Physiology/function; Sinus node dysfunction