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[The effects of PDK1-Akt signaling pathway intervention on cardiomyocyte HCN4 ion channels]

Z L Han1, X Wu1, X H Liu1

  • 1Department of Cardiology, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China.

Zhonghua Xin Xue Guan Bing Za Zhi
|November 19, 2020
PubMed

Insights

The 3-phosphate dependent protein kinase 1-protein kinase B (PDK1-Akt) pathway regulates cardiac hyperpolarized activated cyclic nucleotide gated 4 (HCN4) ion channels. Inhibiting PDK1 increases HCN4 expression and function, while activating Akt partially reverses this effect.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Ion Channel Physiology

Background:

  • Cardiac hyperpolarized activated cyclic nucleotide gated 4 (HCN4) ion channels are crucial for heart rhythm.
  • The 3-phosphate dependent protein kinase 1-protein kinase B (PDK1-Akt) signaling pathway plays a role in cellular processes.
  • Understanding the regulation of HCN4 channels is important for cardiac electrophysiology.

Purpose of the Study:

  • To investigate the role of the PDK1-Akt signaling pathway in regulating HCN4 ion channel transcription, expression, and function.
  • To elucidate the molecular mechanisms underlying PDK1-Akt pathway involvement in HCN4 channel modulation.

Main Methods:

  • Utilized wild-type and heart-specific PDK1 knockout mice atrial myocytes.
  • Employed techniques including qRT-PCR, Western blot, whole-cell patch clamp, and immunofluorescence.
  • Manipulated PDK1 levels via short hairpin RNA (shRNA) and modulated Akt activity using SC79 agonist and GSK2334470.

Main Results:

  • PDK1 knockout and knockdown significantly increased HCN4 mRNA and protein expression, as well as HCN current density.
  • Activation of Akt with SC79 partially reversed the effects of PDK1 knockdown on HCN4 expression and function.
  • GSK2334470 treatment also led to increased HCN4 expression.

Conclusions:

  • The PDK1-Akt signaling pathway is a key regulator of HCN4 ion channel transcription, expression, and function in atrial myocytes.
  • Modulation of this pathway offers potential therapeutic targets for cardiac rhythm disorders.
Keywords:
AktHCN4Myocytes, cardiacPDK1

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