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

AMPK directly phosphorylates HCN4 at Ser1157 in the C terminus as a posttranslational modification.

• Ser1157 was identified as the specific phosphorylation site on the HCN4 C terminus targeted by AMPK.
• This phosphorylation event was characterized as a posttranslational modification mediated by AMPK.
• The phosphorylation at Ser1157 was associated with decreased HCN4 membrane expression.
• This mechanism was identified as distinct from previously described cardiac remodeling effects of AMPK activation.

AMPK-mediated phosphorylation of HCN4 at Ser1157 is associated with decreased HCN4 membrane expression.

• Phosphorylation of Ser1157 correlated with a reduction in HCN4 channel expression at the cell membrane.
• Decreased membrane expression of HCN4 contributes to altered electrophysiological properties of cardiac pacemaker cells.
• This reduction in HCN4 membrane expression was identified as contributing to sinus bradycardia.
• The mechanism represents a direct posttranslational regulatory pathway for HCN4 channel modulation.

AMPK is constitutively activated in aged mice but not in young mice.

• Constitutive AMPK activation was observed in aged mice, in contrast to young mice where this was not present.
• This age-dependent difference in AMPK activation status was identified as a key distinguishing feature between young and old animals.
• The finding establishes an age-related change in the baseline activity state of AMPK in cardiac tissue.
• This constitutive activation in aged mice correlates with the development of intrinsic bradycardia.

Constitutive AMPK activation in aged mice correlates with increased development of intrinsic bradycardia.

• Aged mice with constitutive AMPK activation showed increased intrinsic bradycardia compared to young mice.
• The correlation between AMPK activation and intrinsic bradycardia provides a mechanistic basis for age-related changes in cardiac rhythm.
• Intrinsic bradycardia in this context refers to bradycardia arising from changes within the pacemaker cells themselves rather than extrinsic regulation.
• These findings link the AMPK-HCN4 phosphorylation axis to age-related sinus node dysfunction.

Previous work had established that AMPK activation leads to sinus bradycardia through cardiac remodeling involving decreased HCN4 membrane expression, but the underlying mechanism was previously unclear.

• Prior research demonstrated that AMPK activation results in sinus bradycardia.
• The previously described mechanism involved cardiac remodeling with a decrease in HCN4 membrane expression.
• The molecular mechanism underlying this decrease in HCN4 membrane expression had remained unclear prior to this study.
• The current study clarifies this mechanism by identifying direct phosphorylation of HCN4 at Ser1157 by AMPK.

HCN4 dysfunctional behavior is among the major factors contributing to sinus node disease, a primary cause of pacemaker implantation.

• Sinus node disease is identified as a primary cause requiring pacemaker implantation.
• HCN4 channel dysfunction is described as among the major contributing factors to sinus node disease.
• HCN4 channels in pacemaker myocytes are essential for maintaining physiological cardiac rhythm.
• Understanding HCN4 regulation is therefore clinically relevant to cardiac arrhythmia management.