title: UCH-L1 inhibition involved in CREB dephosphorylation in hippocampal slices.
abstract: Ubiquitin C-terminal hydrolase L1 (UCH-L1) is abundantly expressed in the brain and is critical for the normal function of synapses. cAMP response element binding protein (CREB) is a transcription factor which initiates the expression of proteins that related to the regulation of synaptic plasticity and memory function. Studies have shown that UCH-L1 can influence the expression and activity of CREB, but the underlying mechanisms remain unclear. In this study, we used UCH-L1 inhibitor LDN to treat mice hippocampal slices and found that UCH-L1 inhibition caused the dephosphorylation of CREB at Ser133 site. Meanwhile, hyperphosphorylation of microtubule-associated protein tau; increased expression of synaptic protein components of PSD-95 and synapsin-1, and decreased activity of tyrosine kinase Fyn were observed after UCH-L1 inhibition. Moreover, all these alternations have an influence on the normal function of N-methyl-D-aspartate (NMDA) receptor NR2B subunit which is likely to result in the dephosphorylation of CREB. We also found that LDN treatment mediated protein kinase A (PKA) deactivation was involved in the dephosphorylation of CREB. Thus, our study introduces a novel possible mechanism for elaborating the effects of UCH-L1 inhibition on the CREB activity and the implicated signaling pathways.
authors: Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Science, Central China Normal University, Number 152, Luoyu Road, Wuhan, 430079, China.
authors: Min
authors: M
authors: Xie
authors: Shao-Hui
authors: SH
authors: Wang
authors: Zhi-Min
authors: ZM
authors: Lu
authors: Ying
authors: Y
authors: Pan
authors: Qi-Cai
authors: QC
authors: Chen
authors: Xiao-Mei
authors: XM
authors: Liao
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010091:Oximes / Q000494:pharmacology; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D016704:Synapsins / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D004791:Enzyme Inhibitors; D007211:Indoles; C525086:LDN 57444; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D010091:Oximes; D016194:Receptors, N-Methyl-D-Aspartate; D016704:Synapsins; D016875:tau Proteins; D051076:Proto-Oncogene Proteins c-fyn; D017868:Cyclic AMP-Dependent Protein Kinases; D051528:Guanylate Kinases; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse