Activity-dependent proteolytic cleavage of neuroligin-1

Kunimichi Suzuki; Yukari Hayashi; Soichiro Nakahara; Hiroshi Kumazaki; Johannes Prox; Keisuke Horiuchi; Mingshuo Zeng; Shun Tanimura; Yoshitake Nishiyama; Satoko Osawa; Atsuko Sehara-Fujisawa; Paul Saftig; Satoshi Yokoshima; Tohru Fukuyama; Norio Matsuki; Ryuta Koyama; Taisuke Tomita; Takeshi Iwatsubo

doi:10.1016/j.neuron.2012.10.003

Activity-dependent proteolytic cleavage of neuroligin-1

Neuron. 2012 Oct 18;76(2):410-22. doi: 10.1016/j.neuron.2012.10.003. Epub 2012 Oct 17.

Authors

Kunimichi Suzuki¹, Yukari Hayashi, Soichiro Nakahara, Hiroshi Kumazaki, Johannes Prox, Keisuke Horiuchi, Mingshuo Zeng, Shun Tanimura, Yoshitake Nishiyama, Satoko Osawa, Atsuko Sehara-Fujisawa, Paul Saftig, Satoshi Yokoshima, Tohru Fukuyama, Norio Matsuki, Ryuta Koyama, Taisuke Tomita, Takeshi Iwatsubo

Affiliation

¹ Department of Neuropathology and Neuroscience, The University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113-0033, Japan.

PMID: 23083742
DOI: 10.1016/j.neuron.2012.10.003

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAM Proteins / deficiency
ADAM10 Protein
Amyloid Precursor Protein Secretases / deficiency
Amyloid Precursor Protein Secretases / metabolism
Animals
Animals, Newborn
Biotinylation
Calcium-Binding Proteins
Cell Adhesion Molecules, Neuronal / genetics
Cell Adhesion Molecules, Neuronal / metabolism*
Cells, Cultured
Cerebellum / metabolism
Dendritic Spines / metabolism
Dipeptides / pharmacology
Disease Models, Animal
Embryo, Mammalian
Enzyme Inhibitors / pharmacology
Gene Expression Regulation / drug effects
Gene Expression Regulation / genetics
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Hippocampus / cytology
Humans
Male
Membrane Proteins / deficiency
Mice
Mice, Inbred BALB C
Mice, Knockout
Muscarinic Agonists / toxicity
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neural Cell Adhesion Molecules / metabolism
Neurons / ultrastructure
Organ Culture Techniques
Pilocarpine / toxicity
Proteolysis*
RNA Interference / physiology
Rats
Rats, Wistar
Status Epilepticus / chemically induced
Status Epilepticus / metabolism
Status Epilepticus / pathology
Synaptosomes / drug effects
Synaptosomes / metabolism
Transfection

Substances

Calcium-Binding Proteins
Cell Adhesion Molecules, Neuronal
Dipeptides
Enzyme Inhibitors
Membrane Proteins
Muscarinic Agonists
N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
Nerve Tissue Proteins
Neural Cell Adhesion Molecules
Nrxn1 protein, mouse
neuroligin 1
neuroligin 2
Pilocarpine
Green Fluorescent Proteins
Amyloid Precursor Protein Secretases
ADAM Proteins
ADAM10 Protein
Adam10 protein, mouse