PMID- 28543279
OWN - NLM
STAT- MEDLINE
DCOM- 20170907
LR  - 20190125
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 142
IP  - 4
DP  - 2017 Aug
TI  - Role of AMPA receptors in homocysteine-NMDA receptor-induced crosstalk between 
      ERK and p38 MAPK.
PG  - 560-573
LID - 10.1111/jnc.14078 [doi]
AB  - Homocysteine, a metabolite of the methionine cycle has been reported to play a 
      role in neurotoxicity through activation of N-methyl-d-aspartate receptors 
      (NMDAR)-mediated signaling pathway. The proposed mechanisms associated with 
      homocysteine-NMDAR-induced neurotoxicity involve a unique signaling pathway that 
      triggers a crosstalk between extracellular signal-regulated kinase (ERK) and p38 
      MAPKs, where activation of p38 MAPK is downstream of and dependent on ERK MAPK. 
      However, the molecular basis of the ERK MAPK-mediated p38 MAPK activation is not 
      understood. This study investigates whether 
      alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) play a 
      role in facilitating the ERK MAPK-mediated p38 MAPK activation. Using surface 
      biotinylation and immunoblotting approaches we show that treatment with 
      homocysteine leads to a decrease in surface expression of GluA2-AMPAR subunit in 
      neurons, but have no effect on the surface expression of GluA1-AMPAR subunit. 
      Inhibition of NMDAR activation with D-AP5 or ERK MAPK phosphorylation with 
      PD98059 attenuates homocysteine-induced decrease in surface expression of 
      GluA2-AMPAR subunit. The decrease in surface expression of GluA2-AMPAR subunit is 
      associated with p38 MAPK phosphorylation, which is inhibited by 1-napthyl acetyl 
      spermine trihydrochloride (NASPM), a selective antagonist of GluA2-lacking Ca(2+) 
      -permeable AMPARs. These results suggest that homocysteine-NMDAR-mediated ERK 
      MAPK phosphorylation leads to a decrease in surface expression of GluA2-AMPAR 
      subunit resulting in Ca(2+) influx through the GluA2-lacking Ca(2+) -permeable 
      AMPARs and p38 MAPK phosphorylation. Cell death assays further show that 
      inhibition of AMPAR activity with 
      2,3-dioxo-6-nitro-1,2,3,4,tetrahydrobenzoquinoxaline-7-sulfonamide 
      (NBQX)/6-cyano-7-nitroquinoxaline-2,3, -dione (CNQX) or GluA2-lacking Ca(2+) 
      -permeable AMPAR activity with NASPM attenuates homocysteine-induced 
      neurotoxicity. We have identified an important mechanism involved in 
      homocysteine-induced neurotoxicity that highlights the intermediary role of 
      GluA2-lacking Ca(2+) -permeable AMPARs in the crosstalk between ERK and p38 
      MAPKs.
CI  - (c) 2017 International Society for Neurochemistry.
FAU - Poddar, Ranjana
AU  - Poddar R
AUID- ORCID: 0000-0002-8459-5560
AD  - Department of Neurology, University of New Mexico Health Sciences Center, 
      University of New Mexico, Albuquerque, New Mexico, USA.
FAU - Chen, Alexandria
AU  - Chen A
AD  - Department of Neurology, University of New Mexico Health Sciences Center, 
      University of New Mexico, Albuquerque, New Mexico, USA.
FAU - Winter, Lucas
AU  - Winter L
AD  - Department of Neurology, University of New Mexico Health Sciences Center, 
      University of New Mexico, Albuquerque, New Mexico, USA.
FAU - Rajagopal, Sathyanarayanan
AU  - Rajagopal S
AD  - Department of Neurology, University of New Mexico Health Sciences Center, 
      University of New Mexico, Albuquerque, New Mexico, USA.
FAU - Paul, Surojit
AU  - Paul S
AD  - Department of Neurology, University of New Mexico Health Sciences Center, 
      University of New Mexico, Albuquerque, New Mexico, USA.
LA  - eng
GR  - R01 NS059962/NS/NINDS NIH HHS/United States
GR  - R01 NS083914/NS/NINDS NIH HHS/United States
GR  - R21 NS065343/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20170629
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 6384-92-5 (N-Methylaspartate)
RN  - 77521-29-0 (alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Cell Death/drug effects
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Hippocampus/drug effects/metabolism
MH  - Homocysteine/metabolism
MH  - N-Methylaspartate/pharmacology
MH  - Neurons/drug effects/metabolism
MH  - Rats
MH  - Receptors, AMPA/*metabolism
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Signal Transduction
MH  - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/*pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/*metabolism
PMC - PMC5554079
MID - NIHMS878779
OTO - NOTNLM
OT  - ERK MAPK
OT  - GluA2-AMPA receptors
OT  - NMDA receptors
OT  - homocysteine
OT  - neurotoxicity
OT  - p38 MAPK
COIS- CONFLICT OF INTEREST DISCLOSURE: The authors have no conflict of interest.
EDAT- 2017/05/26 06:00
MHDA- 2017/09/08 06:00
PMCR- 2018/08/01
CRDT- 2017/05/26 06:00
PHST- 2017/02/23 00:00 [received]
PHST- 2017/04/28 00:00 [revised]
PHST- 2017/05/09 00:00 [accepted]
PHST- 2017/05/26 06:00 [pubmed]
PHST- 2017/09/08 06:00 [medline]
PHST- 2017/05/26 06:00 [entrez]
PHST- 2018/08/01 00:00 [pmc-release]
AID - 10.1111/jnc.14078 [doi]
PST - ppublish
SO  - J Neurochem. 2017 Aug;142(4):560-573. doi: 10.1111/jnc.14078. Epub 2017 Jun 29.