title: CPG2 Recruits Endophilin B2 to the Cytoskeleton for Activity-Dependent Endocytosis of Synaptic Glutamate Receptors.
abstract: Internalization of glutamate receptors at the postsynaptic membrane via clathrin-mediated endocytosis (CME) is a key mechanism for regulating synaptic strength. A role for the F-actin cytoskeleton in CME is well established, and recently, PKA-dependent association of candidate plasticity gene 2 (CPG2) with the spine-cytoskeleton has been shown to mediate synaptic glutamate receptor internalization. Yet, how the endocytic machinery is physically coupled to the actin cytoskeleton to facilitate glutamate receptor internalization has not been demonstrated. Moreover, there has been no distinction of endocytic-machinery components that are specific to activity-dependent versus constitutive glutamate receptor internalization. Here, we show that CPG2, through a direct physical interaction, recruits endophilin B2 (EndoB2) to F-actin, thus anchoring the endocytic machinery to the spine cytoskeleton and facilitating glutamate receptor internalization. Regulation of CPG2 binding to the actin cytoskeleton by protein kinase A directly impacts recruitment of EndoB2 and clathrin. Specific disruption of EndoB2 or the CPG2-EndoB2 interaction impairs activity-dependent, but not constitutive, internalization of both NMDA- and AMPA-type glutamate receptors. These results demonstrate that, through direct interactions with F-actin and EndoB2, CPG2 physically bridges the spine cytoskeleton and the endocytic machinery, and this tripartite association is critical specifically for activity-dependent CME of synaptic glutamate receptors.
authors.affiliation: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Loebrich
authors.affiliation: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Marc Robert
authors.initials: MR
authors.lastname: Benoit
authors.affiliation: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Jaclyn Aleksandra
authors.initials: JA
authors.lastname: Konopka
authors.affiliation: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Jeffrey Richard
authors.initials: JR
authors.lastname: Cottrell
authors.affiliation: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139, USA. Electronic address: nedivi@mit.edu.
authors.forename: Elly
authors.initials: E
authors.lastname: Nedivi
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D004622:Embryo, Mammalian; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D002966:Clathrin; C098787:Cpg2 protein, rat; D009419:Nerve Tissue Proteins; D017470:Receptors, Glutamate; C000611964:endophilin B2, rat