title: PICK1-ICA69 heteromeric BAR domain complex regulates synaptic targeting and surface expression of AMPA receptors.
abstract: The trafficking of AMPA-type glutamate receptors to and from synapses is an important mechanism underlying synaptic plasticity, a cellular model of learning and memory. PICK1 (protein interacts with C-kinase 1) is a peripheral membrane protein that interacts with AMPA receptors and regulates their trafficking. PICK1 contains a PDZ (PSD-95/Dlg/ZO1) domain and a BAR (Bin/amphiphysin/Rvs) domain. The PDZ domain of PICK1 interacts with the intracellular C-terminal tails of AMPA receptors, while the BAR domain binds to lipid membranes. Both the AMPA receptor interaction and the lipid binding of PICK1 are important to AMPA receptor trafficking and synaptic plasticity. Here, we identified ICA69 (islet cell autoantigen 69 kDa), another BAR-domain-containing protein, as the major binding partner of PICK1. Over three-fourths of ICA69 and PICK1 associate with each other in the brain. The BAR domain of ICA69 also binds to liposomes and forms heteromeric BAR domain complexes with PICK1. ICA69 coexpresses with PICK1 in different tissues and at various developmental stages. In neurons, although ICA69 colocalizes well with PICK1 in cell bodies and dendrites, it is surprisingly absent from synapses, where PICK1 is enriched. Furthermore, overexpression of ICA69 redistributes PICK1 from synapses to dendrites. ICA69 also disrupts the PICK1-induced clustering of AMPA receptors and reduces synaptic targeting and surface expression of the receptors. ICA69 regulates AMPA receptor trafficking by forming heteromeric BAR domain complexes with PICK1 and preventing formation of PICK1 homomeric complexes. Together, our results suggest that the switch from ICA69-PICK1 heteromeric complexes to PICK1-PICK1 homomeric complexes could be an important mechanism regulating synaptic targeting and surface expression of AMPA receptors.
authors.affiliation: Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Cao
authors.forename: Junyu
authors.initials: J
authors.lastname: Xu
authors.forename: Chong
authors.initials: C
authors.lastname: Shen
authors.forename: Chuen
authors.initials: C
authors.lastname: Kam
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.forename: Jun
authors.initials: J
authors.lastname: Xia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000096:biosynthesis* / Q000235:genetics; D013569:Synapses / Q000378:metabolism* / Q000502:physiology
chemical_list: D001324:Autoantigens; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C490184:Ica1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C091822:Prkcabp protein, mouse; D018091:Receptors, AMPA; C075637:amphiphysin