| Author |
Wang, Y. Rao, W. Zhang, C. Liu, M-D Han, F. Yao, L-b Han, H. Luo, P. Su, N. Fei, Z. |
| Description |
Author Affiliation: Wang Y ( 1] Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China [2] Department of Neurosurgery, Wuhan Zhong Xin Hospital, Wuhan, P.R. China.); Rao W ( Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.); Zhang C ( Department of Neurology, Second Artillery General Hospital of PLA, Beijing, P.R. China.); Zhang C ( Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.); Liu MD ( Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.); Han F ( Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.); Yao LB ( Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an, P.R. China.); Han H ( Department of Medical Genetics and Developmental Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, P.R. China.); Luo P ( Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.); Su N ( Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.); Fei Z ( Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.) |
| Abstract |
Excessive N-methyl-D-aspartate receptor (NMDAR) activation and the resulting activation of neuronal nitric oxide synthase (nNOS) cause neuronal injury. Homer1b/c facilitates NMDAR-PSD95-nNOS complex interactions, and Homer1a is a negative competitor of Homer1b/c. We report that Homer1a was both upregulated by and protected against NMDA-induced neuronal injury in vitro and in vivo. The neuroprotective activity of Homer1a was associated with NMDA-induced Ca2+ influx, oxidative stress and the resultant downstream signaling activation. Additionally, we found that Homer1a functionally regulated NMDAR channel properties in neurons, but did not regulate recombinant NR1/NR2B receptors in HEK293 cells. Furthermore, we found that Homer1a detached the physical links among NR2B, PSD95 and nNOS and reduced the membrane distribution of NMDAR. NMDA-induced neuronal injury was more severe in Homer1a homozygous knockout mice (KO, Homer1a-/-) when compared with NMDA-induced neuronal injury in wild-type mice (WT, Homer1a+/+). Additionally, Homer1a overexpression in the cortex of Homer1a-/- mice alleviated NMDA-induced neuronal injury. These findings suggest that Homer1a may be a key neuroprotective endogenous molecule that protects against NMDA-induced neuronal injury by disassembling NR2B-PSD95-nNOS complexes and reducing the membrane distribution of NMDARs. |
