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The PKC/NOX/ROS and PYK2/MEK/ERK/PARP signalling pathways drive TRPM2 channel activation induced by non-cytolytic

Sharifah Alawieyah Syed Mortadza1,2,3, Nur Zulaikha Mohamad Zahir2, Chew Tze Wei2

  • 1Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, Xinxiang Medical University, Xinxiang, People's Republic of China.

Redox Report : Communications in Free Radical Research
|May 16, 2025
PubMed
Abstract

Insights

Oxidative stress activates microglia TRPM2 channels via a positive feedback loop involving PKC/NOX-mediated ROS and Ca2+ signaling. This mechanism drives microglial activation without causing cell death.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Immunology

Background:

  • Microglia are key immune cells in the central nervous system.
  • Oxidative stress is implicated in neuroinflammation and neurodegenerative diseases.
  • TRPM2 channels play a role in microglial inflammatory responses.

Purpose of the Study:

  • To investigate the signaling mechanism of TRPM2 channel activation by non-cytolytic oxidative stress in microglia.
  • To elucidate the role of reactive oxygen species (ROS) and calcium signaling in this process.

Main Methods:

  • Primary microglia from wild-type and TRPM2-knockout mice were exposed to hydrogen peroxide (H2O2).
  • Assessed morphological changes, intracellular calcium ([Ca2+]c), ROS generation, and the impact of pathway inhibitors.
  • Examined poly (ADP-ribose) polymerase (PARP) activation.

Main Results:

  • H2O2 induced microglial morphological changes and increased [Ca2+]c in wild-type but not TRPM2-knockout cells.
  • ROS generation was dependent on protein kinase C (PKC) and NADPH oxidases (NOX).
  • TRPM2 activation and downstream signaling via PYK2/MEK/ERK were crucial for the response.

Conclusions:

  • A positive feedback mechanism exists between PKC/NOX-mediated ROS and TRPM2-mediated Ca2+ signaling.
  • This feedback loop drives TRPM2 channel activation during non-cytolytic oxidative stress.
  • TRPM2 channel activation is essential for oxidative stress-induced microglial activation.
Keywords:
ERKNOXOxidative stressPARP-1PKCPYK2TRPM2microglia

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