Cohesin-protein Shugoshin-1 controls cardiac automaticity via HCN4 pacemaker channel

Donghai Liu, Andrew Taehun Song, Xiaoyan Qi, Patrick Piet Vliet, Jiening Xiao, Feng Xiong, Gregor Andelfinger and Stanley Nattel ()
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Donghai Liu: Université de Montréal
Andrew Taehun Song: McGill University
Xiaoyan Qi: Université de Montréal
Patrick Piet Vliet: Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal
Jiening Xiao: Université de Montréal
Feng Xiong: Université de Montréal
Gregor Andelfinger: Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal
Stanley Nattel: Université de Montréal

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22737-5

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