Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5.
Metabotropic glutamate receptors (mGluRs) 1-8 are G protein-coupled receptors (GPCRs) that modulate excitatory neurotransmission, neurotransmitter release, and synaptic plasticity. PKC regulates many aspects of mGluR function, including protein-protein interactions, Ca(2+) signaling, and receptor desensitization. However, the mechanisms by which PKC regulates mGluR function are poorly understood. We have now identified calmodulin (CaM) as a dynamic regulator of mGluR5 trafficking. We show that the major PKC phosphorylation site on the intracellular C terminus of mGluR5 is serine 901 (S901), and phosphorylation of this residue is up-regulated in response to both receptor and PKC activation. In addition, S901 phosphorylation inhibits mGluR5 binding to CaM, decreasing mGluR5 surface expression. Furthermore, blocking PKC phosphorylation of mGluR5 on S901 dramatically affects mGluR5 signaling by prolonging Ca(2+) oscillations. Thus, our data demonstrate that mGluR5 activation triggers phosphorylation of S901, thereby directly linking PKC phosphorylation, CaM binding, receptor trafficking, and downstream signaling.
Lee
Jeong Ho
JH
Department of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
Lee
Jinu
J
Choi
Kyu Yeong
KY
Hepp
Regine
R
Lee
Jae-Youn
JY
Lim
Mi Kyung
MK
Chatani-Hinze
Mayumi
M
Roche
Paul A
PA
Kim
Dong Goo
DG
Ahn
Young Soo
YS
Kim
Chul Hoon
CH
Roche
Katherine W
KW
D000818:Animals; D020013:Calcium Signaling; D002147:Calmodulin / Q000502:physiology*; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
D002147:Calmodulin; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D011493:Protein Kinase C