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Rho mediates calcium-dependent activation of p38alpha and subsequent excitotoxic cell death

Maria M Semenova1, Anu M J Mäki-Hokkonen, Jiong Cao

  • 1Department of Neurobiology, A.I. Virtanen Institute, University of Kuopio, Kuopio FIN 70211, Finland.

Nature Neuroscience
|March 21, 2007
PubMed

Insights

Rho GTPase is crucial in excitotoxic neuronal death, a process implicated in neurological disorders. This study reveals Rho

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Excitotoxic neuronal death, linked to neurological disorders, involves calcium influx and stress-activated protein kinases (SAPKs).
  • Previous research suggested roles for Rho-family GTPases in neuronal death and regeneration inhibition.

Purpose of the Study:

  • To investigate the role of Rho GTPase in excitotoxic neuronal death.
  • To determine if Rho activation is a prerequisite for glutamate-induced neuronal death.

Main Methods:

  • Activation of Rho in rat neurons under conditions of elevated intracellular calcium.
  • Assessment of Rho activation in mouse cerebral cortex during ischemia.
  • Analysis of RhoA's effect on p38alpha activation and neuronal death in primary neuronal cultures.

Main Results:

  • Rho GTPase is activated by elevated intracellular calcium and ischemia.
  • Rho is essential for glutamate-induced p38alpha activation and subsequent neuronal death.
  • Expression of active RhoA alone induced neuronal death, sensitive to Bcl-2, indicating sufficiency in the excitotoxic pathway.

Conclusions:

  • Rho GTPase is a critical mediator of excitotoxic neuronal death.
  • Rho activation is a key event in the pathway leading to neuronal death under excitotoxic conditions.

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