title: Activity-dependent alpha-cleavage of nectin-1 is mediated by a disintegrin and metalloprotease 10 (ADAM10).
abstract: Nectin-1 is known to undergo ectodomain shedding by alpha-secretase and subsequent proteolytic processing by gamma-secretase. How secretase-mediated cleavage of nectin-1 is regulated in neuronal cells and how nectin-1 cleavage affects synaptic adhesion is poorly understood. We have investigated alpha-and gamma-secretase-mediated processing of nectin-1 in primary cortical neurons and identified which protease acts as a alpha-secretase. We report here that NMDA receptor activation, but not stimulation of AMPA or metabotropic glutamate receptors, resulted in robust alpha- and gamma-secretase cleavage of nectin-1 in mature cortical neurons. Cleavage of nectin-1 required influx of Ca(2+) through the NMDA receptor, and activation of calmodulin, but was not dependent on calcium/calmodulin-dependent protein kinase II (CaMKII) activation. We found that ADAM10 is the major secretase responsible for nectin-1 ectodomain cleavage in neurons and the brain. These observations suggest that alpha- and gamma-secretase processing of nectin-1 is a Ca(2+)/calmodulin-regulated event that occurs under conditions of activity-dependent synaptic plasticity and ADAM10 and gamma-secretase are responsible for these cleavage events.
authors.affiliation: Neuroscience Department, Georgetown University Medical Center, Washington, D. C. 20057, USA.
authors.forename: Jinsook
authors.initials: J
authors.lastname: Kim
authors.forename: Christina
authors.initials: C
authors.lastname: Lilliehook
authors.forename: Amanda
authors.initials: A
authors.lastname: Dudak
authors.forename: Johannes
authors.initials: J
authors.lastname: Prox
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Federoff
authors.forename: Seung T
authors.initials: ST
authors.lastname: Lim
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D000075983:Nectins; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D002147:Calmodulin; D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C542371:ADAM10 protein, rat; C491234:Adam10 protein, mouse; D002118:Calcium