Abstract
Endogenous cardiac pacemaker function regulates the rate and rhythm of cardiac contraction. The mutation p.Lys23Glu in the cohesin protein Shugoshin-1 causes severe heart arrhythmias due to sinoatrial node dysfunction and a debilitating gastrointestinal motility disorder, collectively termed the Chronic Atrial and Intestinal Dysrhythmia Syndrome, linking Shugoshin-1 and pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation channel 4 (HCN4) is the predominant pacemaker ion-channel in the adult heart and carries the majority of the “funny” current, which strongly contributes to diastolic depolarization in pacemaker cells. Here, we study the mechanism by which Shugoshin-1 affects cardiac pacing activity with two cell models: neonatal rat ventricular myocytes and Chronic Atrial and Intestinal Dysrhythmia Syndrome patient-specific human induced pluripotent stem cell derived cardiomyocytes. We find that Shugoshin-1 interacts directly with HCN4 to promote and stabilize cardiac pacing. This interaction enhances funny-current by optimizing HCN4 cell-surface expression and function. The clinical p.Lys23Glu mutation leads to an impairment in the interaction between Shugoshin-1 and HCN4, along with depressed funny-current and dysrhythmic activity in induced pluripotent stem cell derived cardiomyocytes derived from Chronic Atrial and Intestinal Dysrhythmia Syndrome patients. Our work reveals a critical non-canonical, cohesin-independent role for Shugoshin-1 in maintaining cardiac automaticity and identifies potential therapeutic avenues for cardiac pacemaking disorders, in particular Chronic Atrial and Intestinal Dysrhythmia Syndrome.
Highlights
Endogenous cardiac pacemaker function regulates the rate and rhythm of cardiac contraction
To determine whether Shugoshin 1 (SGO1) might play a direct role in cellular automaticity, we investigated the effects of ectopic expression of SGO1 and the mutated SGO1-K23E protein on the automaticity of cultured neonatal rat ventricular myocyte (NRVM) monolayers
We found that SGO1-WT transduced NRVMs had a higher percentage of spontaneously beating cultures compared to control and SGO1K23E transduced NRVMs (Fig. 1a)
Summary
Endogenous cardiac pacemaker function regulates the rate and rhythm of cardiac contraction. The clinical p.Lys23Glu mutation leads to an impairment in the interaction between Shugoshin-1 and HCN4, along with depressed funny-current and dysrhythmic activity in induced pluripotent stem cell derived cardiomyocytes derived from Chronic Atrial and Intestinal Dysrhythmia Syndrome patients. Mutations in cohesin core proteins, NIPBL, ESCO1, and ESCO2 acetyltransferases, or Histone Deacetylase 8 (HDAC8) have all been associated with “cohesinopathies”, in which syndrome-specific changes in cell-cycling and/or transcriptional regulation produce craniofacial, neural and cardiac defects, gastrointestinal dysfunction, developmental delay, or premature ageing[1,5,6]. We recently identified a series of patients presenting with a combination of heart-rhythm disorders, mainly very slow rhythms due to failure of endogenous cardiac pacemaking function requiring the implantation of artificial pacemakers, and chronic intestinal pseudo-obstruction (CIPO)[5]. We show that disordered cardiac pacemaker function in CAID syndrome is attributable to disruption by the SGO1-K23E mutation of an SGO1 non-canonical function to enhance the cardiac pacemaker funny current (If)
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