title: Scaffolding protein Homer1a protects against NMDA-induced neuronal injury.
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.
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: W
authors.initials: W
authors.lastname: Rao
authors.affiliation: Department of Neurology, Second Artillery General Hospital of PLA, Beijing, P.R. China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: M-D
authors.initials: MD
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: F
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: L-b
authors.initials: LB
authors.lastname: Yao
authors.affiliation: Department of Medical Genetics and Developmental Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: H
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: P
authors.initials: P
authors.lastname: Luo
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: N
authors.initials: N
authors.lastname: Su
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: Z
authors.initials: Z
authors.lastname: Fei
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein; D005786:Gene Expression Regulation; D051528:Guanylate Kinases / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D000072233:Homer Scaffolding Proteins; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D061251:Primary Cell Culture; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013238:Stereotaxic Techniques
chemical_list: D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D000072233:Homer Scaffolding Proteins; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D051528:Guanylate Kinases; D002118:Calcium