Open AccessDe‐palmitoylation by N‐(tert‐Butyl) hydroxylamine inhibits AMPAR ‐mediated synaptic transmission via affecting receptor distribution in postsynaptic densities
Author(s) -
Xia ZhiXuan,
Shen ZuCheng,
Zhang ShaoQi,
Wang Ji,
Nie TaiLei,
Deng Qiao,
Chen JianGuo,
Wang Fang,
Wu PengFei
Publication year - 2019
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12996
Subject(s) - ampa receptor , palmitoylation , postsynaptic density , microbiology and biotechnology , neurotransmission , chemistry , glutamate receptor , excitatory postsynaptic potential , postsynaptic potential , biology , receptor , biochemistry , cysteine , enzyme
Summary Aims Palmitoylation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors ( AMPAR s) subunits or their “scaffold” proteins produce opposite effects on AMPAR surface delivery. Considering AMPAR s have long been identified as suitable drug targets for central nervous system ( CNS ) disorders, targeting palmitoylation signaling to regulate AMPAR function emerges as a novel therapeutic strategy. However, until now, much less is known about the effect of palmitoylation‐deficient state on AMPAR function. Herein, we set out to determine the effect of global de‐palmitoylation on AMPAR surface expression and its function, using a special chemical tool, N‐(tert‐Butyl) hydroxylamine (NtBu HA ). Methods BS 3 protein cross‐linking, Western blot, immunoprecipitation, patch clamp, and biotin switch assay. Results Bath application of NtBu HA (1.0 mM ) reduced global palmitoylated proteins in the hippocampus of mice. Although NtBu HA (1.0 mM ) did not affect the expression of ionotropic glutamate receptor subunits, it preferentially decreased the surface expression of AMPAR s, not N ‐methyl‐d‐aspartate receptors ( NMDAR s). Notably, NtBu HA (1.0 mM ) reduces AMPAR ‐mediated excitatory postsynaptic currents ( mEPSC s) in the hippocampus. This effect may be largely due to the de‐palmitoylation of postsynaptic density protein 95 ( PSD 95) and protein kinase A‐anchoring proteins, both of which stabilized AMPAR synaptic delivery. Furthermore, we found that changing PSD 95 palmitoylation by NtBu HA altered the association of PSD 95 with stargazin, which interacted directly with AMPAR s, but not NMDARs. Conclusion Our data suggest that the palmitoylation‐deficient state initiated by NtBu HA preferentially reduces AMPAR function, which may potentially be used for the treatment of CNS disorders, especially infantile neuronal ceroid lipofuscinosis (Batten disease).