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Role of AMPA receptors in homocysteine‐NMDA receptor‐induced crosstalk between ERK and p38 MAPK
Author(s) -
Poddar Ranjana,
Chen Alexandria,
Winter Lucas,
Rajagopal Sathyanarayanan,
Paul Surojit
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14078
Subject(s) - mapk/erk pathway , ampa receptor , nmda receptor , microbiology and biotechnology , phosphorylation , p38 mitogen activated protein kinases , chemistry , kinase , biology , receptor , biochemistry
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 MAPK s, 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 α‐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‐ AP 5 or ERK MAPK phosphorylation with PD 98059 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 AMPAR s. 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 AMPAR s 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 AMPAR s in the crosstalk between ERK and p38 MAPK s.