Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memory

被引：47

作者：

Xia, Menghang ^{[1
]}

Huang, Ruili ^{[1
]}

Guo, Vicky ^{[2
]}

Southall, Noel ^{[1
]}

Cho, Ming-Hsuang ^{[1
]}

Inglese, James ^{[1
]}

Austin, Christopher P. ^{[1
]}

Nirenberg, Marshall ^{[2
]}

机构：

[1] NHLBI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA

[2] NHLBI, NIH, Lab Biochem Genet, Bethesda, MD 20892 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 07期

基金：

美国国家卫生研究院;

关键词：

memory enhancer; phosphodiesterase inhibitor; quantitative high-throughput screening; RUBINSTEIN-TAYBI-SYNDROME; ELEMENT-BINDING PROTEIN; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; PHOSPHORYLATED CREB; GENE-TRANSCRIPTION; MOUSE MODEL; INHIBITOR; DROSOPHILA; MICE; PDE4;

D O I：

10.1073/pnas.0813020106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Many studies have implicated the cAMP Response Element Binding (CREB) protein signaling pathway in long-term memory. To identify small molecule enhancers of CREB activation of gene expression, we screened approximate to 73,000 compounds, each at 7-15 concentrations in a quantitative high-throughput screening (qHTS) format, for activity in cells by assaying CREB mediated beta-lactamase reporter gene expression. We identified 1,800 compounds that potentiated CREB mediated gene expression, with potencies as low as 16 nM, comprising 96 structural series. Mechanisms of action were systematically determined, and compounds that affect phosphodiesterase 4, protein kinase A, and cAMP production were identified, as well as compounds that affect CREB signaling via apparently unidentified mechanisms. qHTS folowed by interrogation of pathway targets is an efficient paradigm for lead generation for chemical genomics and drug development.

引用

页码：2412 / 2417

页数：6

共 39 条

[1] Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice:: A model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration [J].