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Mol Psychiatry. 2019 Jan;24(1):145-160. doi: 10.1038/s41380-018-0242-y. Epub 2018 Sep 21.

Isoform-specific cleavage of neuroligin-3 reduces synapse strength.

Author information

1
Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA. michael.bemben@ucsf.edu.
2
Departments of Cellular and Molecular Pharmacology and Physiology, University of California, San Francisco, San Francisco, CA, 94158, USA. michael.bemben@ucsf.edu.
3
Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA.
4
Department of Pharmacology and Physiology, Georgetown University, Washington D.C., WA, 20057, USA.
5
Protein/Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA.
6
Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA.
7
Departments of Cellular and Molecular Pharmacology and Physiology, University of California, San Francisco, San Francisco, CA, 94158, USA.
8
Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA. rochek@ninds.nih.gov.

Abstract

The assembly and maintenance of synapses are dynamic processes that require bidirectional contacts between the pre- and postsynaptic structures. A network of adhesion molecules mediate this physical interaction between neurons. How synapses are disassembled and if there are distinct mechanisms that govern the removal of specific adhesion molecules remain unclear. Here, we report isoform-specific proteolytic cleavage of neuroligin-3 in response to synaptic activity and protein kinase C signaling resulting in reduced synapse strength. Although neuroligin-1 and neuroligin-2 are not directly cleaved by this pathway, when heterodimerized with neuroligin-3, they too undergo proteolytic cleavage. Thus protein kinase C-dependent cleavage is mediated through neuroligin-3. Recent studies on glioma implicate the neuroligin-3 ectodomain as a mitogen. Here we demonstrate: (1) there are mechanisms governing specific adhesion molecule remodeling; (2) neuroligin-3 is a key regulator of neuroligin cleavage events; and (3) there are two cleavage pathways; basal and activity-dependent that produce the mitogenic form of neuroligin-3.

PMID:
30242227
DOI:
10.1038/s41380-018-0242-y

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