Interaction between liprin-alpha and GIT1 is required for AMPA receptor targeting.
Liprin-alpha is a multidomain protein that interacts with the LAR family of receptor protein tyrosine phosphatases and the GRIP/ABP family of AMPA receptor-interacting proteins. Previous studies have indicated that liprin-alpha regulates the development of presynaptic active zones and that the association of liprin-alpha with GRIP is required for postsynaptic targeting of AMPA receptors. However, the underlying molecular mechanisms are not well understood. Here we report that liprin-alpha directly interacts with GIT1, a multidomain protein with GTPase-activating protein activity for the ADP-ribosylation factor family of small GTPases known to regulate protein trafficking and the actin cytoskeleton. Electron microscopic analysis indicates that GIT1 distributes to the region of postsynaptic density (PSD) as well as presynaptic active zones. GIT1 is enriched in PSD fractions and forms a complex with liprin-alpha, GRIP, and AMPA receptors in brain. Expression of dominant-negative constructs interfering with the GIT1-liprin-alpha interaction leads to a selective and marked reduction in the dendritic and surface clustering of AMPA receptors in cultured neurons. These results suggest that the GIT1-liprin-alpha interaction is required for AMPA receptor targeting and that GIT1 may play an important role in the organization of presynaptic and postsynaptic multiprotein complexes.
Ko
Jaewon
J
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
Kim
Seho
S
Valtschanoff
Juli G
JG
Shin
Hyewon
H
Lee
Jae-Ran
JR
Sheng
Morgan
M
Premont
Richard T
RT
Weinberg
Richard J
RJ
Kim
Eunjoon
E
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D001923:Brain Chemistry; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005799:Genes, Dominant; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D011940:Receptor Aggregation / Q000502:physiology; D018091:Receptors, AMPA / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000737:chemistry; D013569:Synapses / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D014162:Transfection; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C485647:GIT1 protein, human; C491310:GRIP1 protein, human; D020690:GTPase-Activating Proteins; C485648:Git1 protein, rat; C491309:Grip1 protein, mouse; C491308:Grip1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C490599:Ppfia4 protein, rat; D021122:Protein Subunits; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins