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Promoting proteostasis by cAMP/PKA and cGMP/PKG.

Md Salim Ahammed1, Xuejun Wang1

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|October 30, 2024
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Summary

Proteasome functional insufficiency drives neurodegeneration and heart failure. Activating protein kinase A (PKA) and PKG may break this cycle by enhancing the ubiquitin-proteasome system (UPS) and clearing misfolded proteins.

Keywords:
heart failureneurodegenerative diseaseprotein kinases, cyclic nucleotide phosphodiesteraseproteotoxicityubiquitin-proteasome system

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Area of Science:

  • Cellular Biology
  • Neuroscience
  • Cardiology

Background:

  • Proteasome functional insufficiency (PFI) is linked to neurodegenerative and heart failure diseases.
  • Aberrant protein aggregation impairs the ubiquitin-proteasome system (UPS), increasing proteotoxic stress (IPTS).
  • This creates a detrimental cycle that exacerbates disease progression.

Purpose of the Study:

  • To review the role of protein kinase A (PKA) and protein kinase G (PKG) in regulating proteostasis via the UPS.
  • To explore strategies for treating diseases associated with increased proteotoxic stress (IPTS).
  • To discuss the potential of targeted PKA and PKG activation for therapeutic benefit.

Main Methods:

  • Literature review of studies on PKA, PKG, UPS, and proteostasis.
  • Analysis of mechanisms by which PKA and PKG influence proteasome activity.
  • Discussion of therapeutic implications for diseases involving PFI and IPTS.

Main Results:

  • PKA activates the proteasome by phosphorylating RPN6/PSMD11.
  • PKG is known to activate the proteasome, but its precise mechanism remains to be elucidated.
  • Augmenting cAMP/PKA and cGMP/PKG signaling pathways shows promise for treating IPTS-related diseases.

Conclusions:

  • Targeted activation of PKA and PKG at proteasome nanodomains could offer a therapeutic strategy.
  • This approach may minimize off-target effects while enhancing proteasome function.
  • Modulating PKA and PKG offers a potential avenue for breaking the vicious cycle in PFI-associated diseases.