Postsynaptic scaffold protein Homer 1a protects against traumatic brain injury via regulating group I metabotropic glutamate receptors.
Traumatic brain injury (TBI) produces excessive glutamate, leading to excitotoxicity via the activation of glutamate receptors. Postsynaptic density scaffold proteins have crucial roles in mediating signal transduction from glutamate receptors to their downstream mediators. Therefore, studies on the mechanisms underlying regulation of excitotoxicity by scaffold proteins can uncover new treatments for TBI. Here, we demonstrated that the postsynaptic scaffold protein Homer 1a was neuroprotective against TBI in vitro and in vivo, and this neuroprotection was associated with its effects on group I metabotropic glutamate receptors (mGluRs). Upon further study, we found that Homer 1a mainly affected neuronal injury induced by mGluR1 activation after TBI and also influenced mGluR5 function when its activity was restored. The ability of Homer 1a to disrupt mGluR-ERK signaling contributed to its ability to regulate the functions of mGluR1 and mGluR5 after traumatic injury. Intracellular Ca(2+) and PKC were two important factors involved in the mediation of mGluR-ERK signaling by Homer 1a. These results define Homer 1a as a novel endogenous neuroprotective agent against TBI.
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
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P
Luo
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
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T
Chen
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Y
Y
Zhao
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
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L
Zhang
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Y
Y
Yang
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
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W
Liu
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
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Li
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
W
W
Rao
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
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S
Dai
Department of Surgery, Boston Veterans Affairs Healthcare System, Boston University School of Medicine, Boston, MA, USA.
J
J
Yang
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
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Z
Fei
D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D020935:MAP Kinase Signaling System; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D018696:Neuroprotective Agents; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium