Role of the internal Shank-binding segment of glutamate receptor delta2 in synaptic localization and cerebellar functions.
Glutamate receptor (GluR) delta2 selectively expressed in cerebellar Purkinje cells (PCs) plays key roles in cerebellar long-term depression (LTD), motor learning and formation of parallel fiber (PF)-PC synapses. We have recently shown that the PDZ [postsynaptic density (PSD)-95/Discs large/zona occludens-1]-binding domain at the C-terminal, the T site, is essential for LTD induction and the regulation of climbing fiber (CF) territory, but is dispensable for synaptic localization of GluRdelta2, PF-PC synapse formation and CF elimination process. To investigate the functional roles of the S segment, the second PDZ-binding domain in the middle of the C-terminal cytoplasmic region, we generated GluRdelta2DeltaS mice carrying mutant GluRdelta2 lacking this segment. The amount of GluRdelta2DeltaS in mutant mice was reduced compared with that of GluRdelta2 in wild-type mice. However, the extent of decrease was much larger in the PSD fractions than in cerebellar homogenates, suggesting the requirement of the S segment for efficient synaptic localization. Furthermore, mismatched PF synapses and free spines emerged and CF-innervation territory on PC dendrites expanded in GluRdelta2DeltaS mice. On the other hand, the performance in the rotarod test was comparable between wild-type and GluRdelta2DeltaS mice. These results suggest that the S segment and T site, the two PDZ-binding domains in the C-terminal cytoplasmic region, are differentially involved in diverse GluRdelta2 functions.
Yasumura
Misato
M
Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Uemura
Takeshi
T
Yamasaki
Miwako
M
Sakimura
Kenji
K
Watanabe
Masahiko
M
Mishina
Masayoshi
M
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D064026:Calbindins; D002531:Cerebellum / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011597:Psychomotor Performance / Q000502:physiology; D017470:Receptors, Glutamate / Q000235:genetics / Q000502:physiology*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D064026:Calbindins; D017470:Receptors, Glutamate; D064030:S100 Calcium Binding Protein G; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; C107913:glutamate receptor delta 2