title: The protein phosphatase 1/2A inhibitor okadaic acid increases CREB and Elk-1 phosphorylation and c-fos expression in the rat striatum in vivo.
abstract: Activation of group I metabotropic glutamate receptors (mGluRs) up-regulates transcription factor cyclic AMP response element-binding protein (CREB) and Elk-1 phosphorylation via extracellular signal-regulated kinase 1/2 (ERK1/2) in the striatum in vivo. Protein phosphatase 1/2A further regulates immediate early gene expression by inactivating (dephosphorylating) CREB. In this study, using semi-quantitative immunohistochemical and western blot analyses and in situ hybridization histochemistry, we found that intrastriatal infusion of the protein phosphatase 1/2A inhibitor okadaic acid (0.005, 0.05 and 0.5 nmol) increased CREB and Elk-1 phosphorylation and c-Fos immunoreactivity in the injected dorsal striatum in a dose-dependent manner. In addition, okadaic acid (0.05 and 0.5 nM) increased c-fos mRNA expression in the dorsal striatum in a dose-dependent manner. Intrastriatal infusion of the group I agonist 3,5-dihydroxyphenylglycine (DHPG) at 100 and 250 nM also increased CREB and Elk-1 phosphorylation. Pre-treatment of okadaic acid (0.05 nm) did not alter DHPG-induced increases in the phosphorylation of the two transcription factors. These data suggest that protein phosphatase 1/2A in striatal neurons is tonically active in dephosphorylating CREB and Elk-1 and thus suppressing constitutive c-fos mRNA and protein expression. Inhibition of the phosphatase 1/2A may contribute to the group I mGluR-regulated phosphorylation of these transcription factors and c-fos expression.
authors.affiliation: Division of Biological Sciences, Pusan National University, Pusan, Korea.
authors.forename: Eun Sang
authors.initials: ES
authors.lastname: Choe
authors.forename: Nikhil K
authors.initials: NK
authors.lastname: Parelkar
authors.forename: Jong Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: Hyun Wook
authors.initials: HW
authors.lastname: Cho
authors.forename: Ho Sung
authors.initials: HS
authors.lastname: Kang
authors.forename: Limin
authors.initials: L
authors.lastname: Mao
authors.forename: John Q
authors.initials: JQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D012118:Resorcinols / Q000494:pharmacology; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D012118:Resorcinols; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D019319:Okadaic Acid; C079215:3,5-dihydroxyphenylglycine; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D005998:Glycine