AMPK-MEDIATED LONG-TERM REGULATION OF HCN4CONTRIBUTES TO AGE-RELATED SINUS BRADYCARDIA

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediates inward depolarizing currents, called If in the heart and Ih in the brain, that contribute to the regulation of neuronal excitability and cardiac rhythm. Among the HCN isotypes, HCN4 stands out for its prominent role in pacemaker activity in the heart where it acts as a key element for the heart rhythm and its adrenergic modulation. Changes in HCN4 activity or in its amount leads to pathological condition characterized by altered heart rhythm known as Sinus Node Dysfunction (SND), which is the most common cause of pacemaker implantation. Therefore, a better understanding of the cellular mechanisms that regulate HCN4 channels will be helpful for the prevention or the treatment of this condition. Among protein kinases, AMPK activation has been shown to induce a cardiac remodeling that leads to sinus bradycardia. In this context, this work highlights a possible mechanism through which AMPK regulates HCN4 channels and explores how this mechanism may be linked to the intrinsic bradycardia typical of aging.