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

Maria M Semenova; Anu M J Mäki-Hokkonen; Jiong Cao; Vladislav Komarovski; K Marjut Forsberg; Milla Koistinaho; Eleanor T Coffey; Michael J Courtney

doi:10.1038/nn1869

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

Nat Neurosci. 2007 Apr;10(4):436-43. doi: 10.1038/nn1869. Epub 2007 Mar 18.

Authors

Maria M Semenova¹, Anu M J Mäki-Hokkonen, Jiong Cao, Vladislav Komarovski, K Marjut Forsberg, Milla Koistinaho, Eleanor T Coffey, Michael J Courtney

Affiliation

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

PMID: 17369826
DOI: 10.1038/nn1869

Abstract

Excitotoxic neuronal death contributes to many neurological disorders, and involves calcium influx and stress-activated protein kinases (SAPKs) such as p38alpha. There is indirect evidence that the small Rho-family GTPases Rac and cdc42 are involved in neuronal death subsequent to the withdrawal of nerve growth factor (NGF), whereas Rho is involved in the inhibition of neurite regeneration and the release of the amyloidogenic Abeta(42) peptide. Here we show that Rho is activated in rat neurons by conditions that elevate intracellular calcium and in the mouse cerebral cortex during ischemia. Rho is required for the rapid glutamate-induced activation of p38alpha and ensuing neuronal death. The ability of RhoA to activate p38alpha was not expected, and it was specific to primary neuronal cultures. The expression of active RhoA alone not only activated p38alpha but also induced neuronal death that was sensitive to the anti-apoptotic protein Bcl-2, showing that RhoA was sufficient to induce the excitotoxic pathway. Therefore, Rho is an essential component of the excitotoxic cell death pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADP Ribose Transferases / metabolism
ADP Ribose Transferases / pharmacology
Animals
Animals, Newborn
Botulinum Toxins / metabolism
Botulinum Toxins / pharmacology
Brain / cytology
Calcium / metabolism*
Cell Death / drug effects
Cell Death / physiology
Cells, Cultured
Dose-Response Relationship, Drug
Enzyme Activation / drug effects
Enzyme Activation / physiology
Enzyme Inhibitors / pharmacology
Excitatory Amino Acid Agonists / pharmacology
Functional Laterality
Glutamic Acid / pharmacology
Ischemia / metabolism
Ischemia / pathology
Mice
Mitogen-Activated Protein Kinase 14 / metabolism*
Models, Molecular
N-Methylaspartate / pharmacology
Neurons / drug effects
Neurons / physiology*
Transfection / methods
cdc42 GTP-Binding Protein / metabolism
rhoA GTP-Binding Protein / physiology*

Substances

Enzyme Inhibitors
Excitatory Amino Acid Agonists
Glutamic Acid
N-Methylaspartate
ADP Ribose Transferases
exoenzyme C3, Clostridium botulinum
Mitogen-Activated Protein Kinase 14
Botulinum Toxins
cdc42 GTP-Binding Protein
rhoA GTP-Binding Protein
Calcium