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Identification of glucose-dependant insulin secretion targets in pancreatic beta cells by combining defined-mechanism compound library screening and siRNA gene silencing.
- Source :
-
Journal of biomolecular screening [J Biomol Screen] 2008 Feb; Vol. 13 (2), pp. 128-34. Date of Electronic Publication: 2008 Jan 23. - Publication Year :
- 2008
-
Abstract
- Identification and validation of novel drug targets continues to be a major bottleneck in drug development, particularly for polygenic complex diseases such as type 2 diabetes. Here, the authors describe an approach that allows researchers to rapidly identify and validate potential drug targets by combining chemical tools and RNA interference technology. As a proof-of-concept study, the known mechanism Sigma LOPAC library was used to screen for glucose-dependent insulin secretion (GDIS) in INS-1 832/13 cells. In addition to several mechanisms that are known to regulate GDIS (such as cyclic adenosine monophosphate-specific phosphodiesterases, adrenoceptors, and Ca(2+) channels), the authors find that several of the dopamine receptor (DRD) antagonists significantly enhance GDIS, whereas DRD agonists profoundly inhibit GDIS. Subsequent siRNA studies in the same cell line indicate that knockdown of DRD2 enhanced GDIS. Furthermore, selective DRD2 antagonists and agonists also enhance or suppress, respectively, GDIS in isolated rat islets. The data support that the approach described here offers a rapid and effective way for target identification and validation.
- Subjects :
- Animals
Cells, Cultured
Dopamine Antagonists pharmacology
Insulin Secretion
Metabolic Networks and Pathways drug effects
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Receptors, Dopamine genetics
Receptors, Dopamine metabolism
Gene Library
Gene Silencing physiology
Glucose pharmacology
Insulin metabolism
Insulin-Secreting Cells metabolism
Metabolic Networks and Pathways genetics
RNA, Small Interfering pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1087-0571
- Volume :
- 13
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of biomolecular screening
- Publication Type :
- Academic Journal
- Accession number :
- 18216393
- Full Text :
- https://doi.org/10.1177/1087057107313763