# AMPK-mediated HCN4 channel phosphorylation contributes to age-related intrinsic bradycardia

## TL;DR

This study shows that AMPK slows heart rate by phosphorylating HCN4 channels, contributing to age-related bradycardia in cardiac pacemaker cells.

## Contribution

The novel finding is that AMPK directly phosphorylates HCN4 at Ser1157, reducing its membrane expression and causing age-related intrinsic bradycardia.

## Key findings

- AMPK phosphorylates HCN4 at Ser1157, decreasing its membrane expression.
- AMPK is constitutively activated in aged mice, correlating with intrinsic bradycardia.
- This mechanism contributes to altered electrophysiological properties in pacemaker cells.

## Abstract

In cardiac pacemaker cells, AMPK activation by AMP in low-energy conditions reduces the If current and slows cardiac rate, an energy-saving mechanism. This work shows that AMPK inhibits HCN4 membrane expression by direct channel phosphorylation, and shows that this process contributes to age-dependent intrinsic rate slowing.

The regulation of the hyperpolarization-activated cyclic nucleotide–gated 4 (HCN4) channels in pacemaker myocytes is essential for maintaining physiological cardiac rhythm. HCN4 dysfunctional behavior is among the major factors contributing to sinus node disease, a primary cause of pacemaker implantation. Previous work has shown that AMP-activated protein kinase (AMPK) activation leads to sinus bradycardia, a process attributable to cardiac remodeling that involves a decrease in HCN4 membrane expression, but the mechanism underlying this event remains unclear. We show here that AMPK can act as a posttranslational effector by phosphorylating Ser1157 at the C terminus of HCN4, a modification associated with a decrease in HCN4 membrane expression contributing to altered electrophysiological properties of cardiac pacemaker cells. Furthermore, we provide evidence that AMPK is constitutively activated in aged, but not young, mice, correlating with an increased development of intrinsic bradycardia. These findings support the view that AMPK is a key player in cardiac rhythm regulation and provide new insights into the molecular mechanisms underlying age-related changes in cardiac rhythm regulation.