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.
Highlights
Dendritic spine shape is continuously modulated by excitatory stimulation
Because nectin-1 is present at excitatory synapses in vitro and in vivo, and localizes at puncta adherentia junctions (PAJs) between pre- and postsynaptic membranes [5, 9], we surmised that shedding of nectin-1 is a regulated event influencing synaptic adhesion under conditions of synaptic plasticity
We examined ectodomain shedding of nectin-1 during synapse formation in primary cortical neurons harvested from 1
Summary
Dendritic spine shape is continuously modulated by excitatory stimulation. This correlation has been suggested to be the cellular basis of memory formation. It has been suggested that neuronal cell adhesion molecules are actively involved in spine remodeling. The shedding of nectin-1 occurs at the synapses in mature hippocampal neurons when the actin cytoskeleton is disrupted [9] This shedding was inhibited by metalloprotease inhibitors in epithelial cells [18], suggesting that a metalloprotease may be involved. Ectodomain shedding and ␥-secretase cleavage of synaptic cell adhesion molecules would comprise a rapid and elegant means by which neurons might remodel spine structure in response to synaptic transmission. It is not well understood how secretase cleavage of synaptic adhesion molecules is regulated by neuronal transmission. Nectin-1 Undergoes Ectodomain Shedding Mediated by ADAM10 explore this area, we have studied nectin-1 processing by ␣- and ␥-secretase in cortical neurons and identified ADAM-10 as the metalloprotease responsible for ␣-secretase activity
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