Activity-regulated N-cadherin endocytosis.
Enduring forms of synaptic plasticity are thought to require ongoing regulation of adhesion molecules, such as N-cadherin, at synaptic junctions. Little is known about the activity-regulated trafficking of adhesion molecules. Here we demonstrate that surface N-cadherin undergoes a surprisingly high basal rate of internalization. Upon activation of NMDA receptors (NMDAR), the rate of N-cadherin endocytosis is significantly reduced, resulting in an accumulation of N-cadherin in the plasma membrane. Beta-catenin, an N-cadherin binding partner, is a primary regulator of N-cadherin endocytosis. Following NMDAR stimulation, beta-catenin accumulates in spines and exhibits increased binding to N-cadherin. Overexpression of a mutant form of beta-catenin, Y654F, prevents the NMDAR-dependent regulation of N-cadherin internalization, resulting in stabilization of surface N-cadherin molecules. Furthermore, the stabilization of surface N-cadherin blocks NMDAR-dependent synaptic plasticity. These results indicate that NMDAR activity regulates N-cadherin endocytosis, providing a mechanistic link between structural plasticity and persistent changes in synaptic efficacy.
Tai
Chin-Yin
CY
Division of Biology 114-96, California Institute of Technology, Pasadena, CA 91125, USA.
Mysore
Shreesh P
SP
Chiu
Cindy
C
Schuman
Erin M
EM
D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells; D015820:Cadherins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D004705:Endocytosis / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000502:physiology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D016194:Receptors, N-Methyl-D-Aspartate; D051176:beta Catenin