Inhibition of protein phosphatase 2B upregulates serine phosphorylation of N-methyl-D-aspartate receptor NR1 subunits in striatal neurons in vivo.
This study investigated the role of protein phosphatase 2B (calcineurin) in regulating phosphorylation of N-methyl-D-aspartate receptor (NMDAR) NR1 subunits and other phosphoproteins in the rat striatum in vivo. In chronically cannulated rats, microinjection of the calcineurin selective inhibitor cyclosporin A increased phosphorylation of NMDAR NR1 subunits at serine 896 and serine 897 in the injected dorsal striatum. The increase in NMDAR NR1 phosphorylation was dose-dependent in a dose range surveyed (0.005, 0.05, and 0.5 nmol). Parallel with increased serine phosphorylation of NR1 subunits, cyclosporin A dose-dependently increased phosphorylation of a Ca2+-sensitive protein kinase, extracellular signal-regulated protein kinase 1/2 (ERK1/2), and a Ca2+/cAMP-sensitive transcription factor, cAMP response element-binding protein (CREB), in the dorsal striatum. Using an immediate early gene product Fos as a reporter of inducible gene expression, cyclosporin A was found to upregulate Fos expression in the dorsal striatum. These results indicate that calcineurin plays an important role in the tonic dephosphorylation of NMDAR NR1 subunits and other two key cytoplasmic and nuclear signaling proteins (ERK1/2 and CREB) in striatal neurons.
Choe
Eun Sang
ES
Department of Biology, Pusan National University, 30 Jangjeon-dong, Kumjeong-gu, Pusan 609-735, Republic of Korea. eschoe@pusan.ac.kr
Shin
Eun Ha
EH
Wang
John Q
JQ
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D003342:Corpus Striatum / Q000166:cytology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015854:Up-Regulation
D065095:Calcineurin Inhibitors; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; C409466:NR1 NMDA receptor; D016761:Oncogene Proteins v-fos; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D016572:Cyclosporine; D048052:Mitogen-Activated Protein Kinase 3; D019703:Calcineurin