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PDK1-AKT signaling pathway regulates the expression and function of cardiac hyperpolarization-activated cyclic

Zhonglin Han1, Xiang Wu1, Yuan Gao1

  • 1Department of Cardiology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China.

Life Sciences
|March 19, 2020
PubMed

Insights

The PDK1-AKT pathway regulates hyperpolarization-activated cyclic nucleotide-modulated channels (HCNs) in atrial myocytes. PDK1 impacts HCN expression, current density, and cell membrane localization, influencing cardiac remodeling.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Ion Channel Physiology

Background:

  • 3-phosphoinositide-dependent protein kinase-1 (PDK1) is implicated in cardiac remodeling and ion channel regulation.
  • The specific role of PDK1 in modulating hyperpolarization-activated cyclic nucleotide-modulated channels (HCNs) is not well understood.

Purpose of the Study:

  • To investigate the regulatory relationship between PDK1 and HCNs in atrial myocytes.
  • To elucidate the involvement of the PDK1-AKT signaling pathway in HCN channel function.

Main Methods:

  • Utilized a heart-specific PDK1 knockout mouse model and neonatal mice.
  • Employed protein kinase B (AKT) inhibitors/agonists, knockdown/overexpression plasmids, immunofluorescence, and patch-clamp electrophysiology.
  • Examined HCN expression and AKT phosphorylation in atrial myocytes.

Main Results:

  • PDK1 knockout or inhibition decreased HCN1 expression and AKT phosphorylation but increased HCN2 and HCN4 levels.
  • PDK1 inhibition/overexpression affected HCN expression, which was reversible by modulating AKT activity.
  • Immunofluorescence and patch-clamp confirmed PDK1's influence on HCNs.

Conclusions:

  • The PDK1-AKT signaling pathway is a key regulator of HCN channels.
  • PDK1 influences HCN mRNA transcription, protein expression, HCN current density, and subcellular localization.
  • This pathway plays a significant role in cardiac ion channel function and potentially pathological remodeling.
Abstract

Keywords:
3-phosphoinositide-dependent protein kinase-1AKTHCNHyperpolarization-activated cyclic nucleotide-modulated channelsPDK1Protein kinase B

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