PT - JOURNAL ARTICLE AU - Groth, Casper AU - Alvord, W. Gregory AU - Quiñones, Octavio A. AU - Fortini, Mark E. TI - Pharmacological Analysis of <em>Drosophila melanogaster</em> γ-Secretase with Respect to Differential Proteolysis of Notch and APP AID - 10.1124/mol.109.062471 DP - 2010 Apr 01 TA - Molecular Pharmacology PG - 567--574 VI - 77 IP - 4 4099 - http://molpharm.aspetjournals.org/content/77/4/567.short 4100 - http://molpharm.aspetjournals.org/content/77/4/567.full SO - Mol Pharmacol2010 Apr 01; 77 AB - The γ-secretase aspartyl protease is responsible for the cleavage of numerous type I integral membrane proteins, including amyloid precursor protein (APP) and Notch. APP cleavage contributes to the generation of toxic amyloid β peptides in Alzheimer's disease, whereas cleavage of the Notch receptor is required for normal physiological signaling between differentiating cells. Mutagenesis studies as well as in vivo analyses of Notch and APP activity in the presence of pharmacological inhibitors indicate that these substrates can be differentially modulated by inhibition of mammalian γ-secretase, although some biochemical studies instead show nearly identical dose-response inhibitor effects on Notch and APP cleavages. Here, we examine the dose-response effects of several inhibitors on Notch and APP in Drosophila melanogaster cells, which possess a homogeneous form of γ-secretase. Four different inhibitors that target different domains of γ-secretase exhibit similar dose-response effects for both substrates, including rank order of inhibitor potencies and effective concentration ranges. For two inhibitors, modest differences in inhibitor dose responses toward Notch and APP were detected, suggesting that inhibitors might be identified that possess some discrimination in their ability to target alternative γ-secretase substrates. These findings also indicate that despite an overall conservation in inhibitor potencies toward different γ-secretase substrates, quantitative differences might exist that could be relevant for the development of therapeutically valuable substrate-specific inhibitors.U.S. Government work not protected by U.S. copyright