Corequirement of PICK1 binding and PKC phosphorylation for stable surface expression of the metabotropic glutamate receptor mGluR7.
The presynaptic metabotropic glutamate receptor (mGluR) mGluR7 modulates excitatory neurotransmission by regulating neurotransmitter release and plays a critical role in certain forms of synaptic plasticity. Although the dynamic regulation of mGluR7 surface expression governs a form of metaplasticity in the hippocampus, little is known about the molecular mechanisms regulating mGluR7 trafficking. We now show that mGluR7 surface expression is stabilized by both PKC phosphorylation and by receptor binding to the PDZ domain-containing protein PICK1. Phosphorylation of mGluR7 on serine 862 (S862) inhibits CaM binding, thereby increasing mGluR7 surface expression and receptor binding to PICK1. Furthermore, in mice lacking PICK1, PKC-dependent increases in mGluR7 phosphorylation and surface expression are diminished, and mGluR7-dependent plasticity at mossy fiber-interneuron hippocampal synapses is impaired. These data support a model in which PICK1 binding and PKC phosphorylation act together to stabilize mGluR7 on the cell surface in vivo.
National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA.
Young Ho
YH
Suh
Kenneth A
KA
Pelkey
Gabriela
G
Lavezzari
Paul A
PA
Roche
Richard L
RL
Huganir
Chris J
CJ
McBain
Katherine W
KW
Roche
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors; D018846:Excitatory Amino Acids; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014162:Transfection / Q000379:methods
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D018846:Excitatory Amino Acids; D009687:Nuclear Proteins; C091822:Prkcabp protein, mouse; D018094:Receptors, Metabotropic Glutamate; C102719:metabotropic glutamate receptor 7; D012694:Serine; D016202:N-Methylaspartate; D011493:Protein Kinase C