期刊
ACS CHEMICAL NEUROSCIENCE
卷 1, 期 4, 页码 325-342出版社
AMER CHEMICAL SOC
DOI: 10.1021/cn900046a
关键词
Neuregulin; ErbB4; automated imaging; neuritogenesis; quinazoline; indolocarbazole
资金
- Stanley Medical Research Institute
- Broad Institute SPARC
- NIMH [1R21MH076146-01, 1R21MH087896-01]
- National Cancer Institute [N01-CO-12400]
Genetic findings have suggested that neuregulin-1 (Nrg1) and its receptor v-erb-a erythroblastic leukemia viral oncogene homologue 4 (ErbB4) may play a role in neuropsychiatric diseases. However, the downstream signaling events and relevant phenotypic consequences of altered Nrg1 signaling in the nervous system remain poorly understood. To identify small molecules for probing Nrg1-ErbB4 signaling, a PC12-cell model was developed and used to perform a live-cell, image-based screen of the effects of small molecules on Nrg1-induced neuritogenesis. By comparison of the resulting phenotypic data to that of a similar screening performed with nerve growth factor (NGF), this multidimensional screen identified compounds that directly inhibit Nrg1-ErbB4 signaling, such as the 4-anilinoquinazoline Iressa (gefitinib), as well as compounds that potentiate Nrg1-ErbB4 signaling, such as the indolocarbazole K-252a. These findings provide new insights into the regulation of Nrg1-ErbB4 signaling events and demonstrate the feasibility of using such a multidimensional, chemical-genetic approach for discovering probes of pathways implicated in neuropsychiatric diseases.
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