Rho mediates calcium-dependent activation of p38alpha and subsequent excitotoxic cell death.
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.
Semenova
Maria M
MM
Department of Neurobiology, A.I. Virtanen Institute, University of Kuopio, Kuopio FIN 70211, Finland.
Mäki-Hokkonen
Anu M J
AM
Cao
Jiong
J
Komarovski
Vladislav
V
Forsberg
K Marjut
KM
Koistinaho
Milla
M
Coffey
Eleanor T
ET
Courtney
Michael J
MJ
D036002:ADP Ribose Transferases / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001905:Botulinum Toxins / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D007839:Functional Laterality; D018698:Glutamic Acid / Q000494:pharmacology; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D008958:Models, Molecular; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D014162:Transfection / Q000379:methods; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D016202:N-Methylaspartate; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D048308:Mitogen-Activated Protein Kinase 14; D001905:Botulinum Toxins; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D002118:Calcium