Activity-dependent proteolytic cleavage of neuroligin-1.
Neuroligin (NLG), a postsynaptic adhesion molecule, is involved in the formation of synapses by binding to a cognate presynaptic ligand, neurexin. Here we report that neuroligin-1 (NLG1) undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment (CTF) in adult rat brains in vivo as well as in neuronal cultures. Pharmacological and genetic studies identified ADAM10 as the major protease responsible for NLG1 shedding, the latter being augmented by synaptic NMDA receptor activation or interaction with soluble neurexin ligands. NLG1-CTF was subsequently cleaved by presenilin/γ-secretase. Secretion of soluble NLG1 was significantly upregulated under a prolonged epileptic seizure condition, and inhibition of NLG1 shedding led to an increase in numbers of dendritic spines in neuronal cultures. Collectively, neuronal activity-dependent proteolytic processing of NLG1 may negatively regulate the remodeling of spines at excitatory synapses.
Department of Neuropathology and Neuroscience, The University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113-0033, Japan.
Kunimichi
K
Suzuki
Yukari
Y
Hayashi
Soichiro
S
Nakahara
Hiroshi
H
Kumazaki
Johannes
J
Prox
Keisuke
K
Horiuchi
Mingshuo
M
Zeng
Shun
S
Tanimura
Yoshitake
Y
Nishiyama
Satoko
S
Osawa
Atsuko
A
Sehara-Fujisawa
Paul
P
Saftig
Satoshi
S
Yokoshima
Tohru
T
Fukuyama
Norio
N
Matsuki
Ryuta
R
Koyama
Taisuke
T
Tomita
Takeshi
T
Iwatsubo
D051722:ADAM Proteins / Q000172:deficiency; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D019921:Biotinylation; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009474:Neurons / Q000648:ultrastructure; D009924:Organ Culture Techniques; D010862:Pilocarpine / Q000633:toxicity; D059748:Proteolysis; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D004151:Dipeptides; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D018721:Muscarinic Agonists; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; C093438:neuroligin 1; C098003:neuroligin 2; D010862:Pilocarpine; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse