Abstract
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 Ca2+ 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.
Highlights
Promising compounds that uncouple postsynaptic scaffold protein PSD-95 from the N-methyl-D-aspartate receptor (NMDAR)-related neurotoxic signaling pathway have demonstrated effective neuroprotection in the treatment of stroke, another severe acute brain injury.[3,4,5] the disruption of glutamate receptor signaling by targeting postsynaptic scaffold proteins provides a novel strategy for inhibiting excitotoxicity caused by Traumatic brain injury (TBI)
This regulatory model has been demonstrated in several neurological diseases, including inflammatory pain[13,14] and fragile X syndrome,[15] which raises the question of how Homer 1a is involved in regulating metabotropic glutamate receptor (mGluR) signaling in TBI
Lentiviral transduction of Flag-tagged Homer 1a (Flag-H1a) increased the expression of Homer 1a protein (Figures 1d and e), which inhibited the reduction of cell viability (Figure 1f), attenuated cytotoxicity (Figure 1g), and cell death (propidium iodide (PI) positive staining) (Figure 1h) in neurons undergoing traumatic injury
Summary
Promising compounds that uncouple postsynaptic scaffold protein PSD-95 from the NMDAR-related neurotoxic signaling pathway have demonstrated effective neuroprotection in the treatment of stroke, another severe acute brain injury.[3,4,5] the disruption of glutamate receptor signaling by targeting postsynaptic scaffold proteins provides a novel strategy for inhibiting excitotoxicity caused by TBI. Overexpression of Homer 1a increased cell viability and decreased cytotoxicity and cell death in neuronal cultures treated with an agonist of group I mGluRs (DHPG), whereas knockdown of Homer 1a enhanced neuronal injury after activation of mGluRs (Figures 3j–l).
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