kt-5720 and 2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline

Presenilin (PS) plays an essential role in intramembranous gamma-secretase processing of amyloid precursor protein (APP) and several membrane-bound proteins. Here we report that selective accumulation of a membrane-tethered deleted in colorectal cancer (DCC) derivative (DCC-alpha) correlates with extensive neurite outgrowth in transfected neuroblastoma cells and axodendritic connectivity associated with increased spine density in cortical neurons derived from PS1(-/-) embryos, as well as wild-type neurons treated with gamma-secretase inhibitors. cAMP-dependent signaling was also increased in both the neuroblastoma and cortical neuron systems. As a physiological consequence of increases in axodendritic connectivity and in the magnitude of cAMP-dependent signaling, short- and long-term glutamatergic synaptic transmission was enhanced in PS-deficient neurons. Together, these results demonstrate for the first time that PS-mediated gamma-secretase activity attenuates receptor-mediated intracellular signaling pathways that are critical in regulating glutamatergic synaptic transmission and memory processes.

Topics: Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Carbamates; Carbazoles; Cell Adhesion Molecules; Cell Line, Tumor; Cell Membrane; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DCC Receptor; Dipeptides; Endopeptidases; Excitatory Postsynaptic Potentials; Genes, DCC; Glutamic Acid; Indoles; Lidocaine; Membrane Proteins; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurites; Neuroblastoma; Neurons; Piperazines; Presenilin-1; Protein Processing, Post-Translational; Pyrroles; Quinoxalines; Rats; Receptors, Cell Surface; Recombinant Fusion Proteins; Second Messenger Systems; Synaptic Transmission; Transfection; Tumor Suppressor Proteins