Presenilin attenuates receptor-mediated signaling and synaptic function.
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.
Parent
Angèle T
AT
Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, USA. aparent@uchicago.edu
Barnes
Natalie Y
NY
Taniguchi
Yoshihito
Y
Thinakaran
Gopal
G
Sisodia
Sangram S
SS
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000075389:DCC Receptor; D004151:Dipeptides / Q000494:pharmacology; D010450:Endopeptidases; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D016163:Genes, DCC; D018698:Glutamic Acid / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational; D011758:Pyrroles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D002219:Carbamates; D002227:Carbazoles; D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; C501910:Dcc protein, mouse; D004151:Dipeptides; D007211:Indoles; C410009:L 685458; D008565:Membrane Proteins; D010879:Piperazines; D053764:Presenilin-1; D011758:Pyrroles; D011810:Quinoxalines; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D005576:Colforsin; C012647:QX-314; D018698:Glutamic Acid; C057416:KT 5720; D008012:Lidocaine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse