Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memory.
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 approximately 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 followed by interrogation of pathway targets is an efficient paradigm for lead generation for chemical genomics and drug development.
Xia
Menghang
M
NIH Chemical Genomics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Huang
Ruili
R
Guo
Vicky
V
Southall
Noel
N
Cho
Ming-Hsuang
MH
Inglese
James
J
Austin
Christopher P
CP
Nirenberg
Marshall
M
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020128:Inhibitory Concentration 50; D008568:Memory; D010766:Phosphorylation; D015398:Signal Transduction; D001618:beta-Lactamases / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D001618:beta-Lactamases