GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-11, Vol.107 (44), p.19038-19043
• Main Authors: Mao, Lifang, Takamiya, Kogo, Thomas, Gareth, Lin, Da-Ting, Huganir, Richard L.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; AMPA receptors; Animals; Binding sites; Biochemistry; Biological Sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cellular biology; Embryos; Endocytosis; Endosomes; Exocytosis - physiology; Gene deletion; GRIP1 protein; HEK293 Cells; Humans; Lethality; Long term depression; Machinery; Mice; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons; Neurons - metabolism; Neuroscience; Physiological regulation; Plasticity (neural); Postsynaptic density proteins; Protein interaction; Protein transport; Protein Transport - physiology; Protein turnover; Proteins; Rats; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Recycling; Rodents; Synapses; trafficking; Waste management; Zonula occludens-1 protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1013494107

PSD-95/SAP90/DLG/ZO-1 (PDZ) domain-mediated protein–protein interactions play important roles in regulating AMPA receptor trafficking and neuronal plasticity. GRIP1 and GRIP2 are homologous multi-PDZ domain-containing proteins that bind to the C-termini of AMPA-R GluA2 and GluA3 subunits. Previous attempts to determine the cellular roles of GRIP1 and GRIP2 in neurons have been complicated by nonspecific reagents, and by the embryonic lethality of conventional GRIP1 KO mice. To circumvent these issues we developed a conditional targeted deletion strategy to knock out GRIP1 in postnatal neurons derived from GRIP2 KO mice. Loss of GRIP1 and 2 did not affect normal AMPA-R steadystate trafficking and endocytosis, but strikingly impaired activitydependent AMPA-R recycling. This previously uncharacterized role for GRIP1 appears to be mediated by novel interactions with the cellular trafficking machinery via the exocyst protein complex. Indeed, disruption of GRIP1-exocyst binding caused a strikingly similar deficit in AMPA-R recycling. Together these findings reveal a previously unidentified role for AMPA-R-GRIP1-exocyst protein complexes in activity-dependent AMPA-R trafficking.