Differential sensitivity of mesencephalic neurons to inhibition of phosphatase 2A

Citation
Gd. Zeevalk et al., Differential sensitivity of mesencephalic neurons to inhibition of phosphatase 2A, J PHARM EXP, 298(3), 2001, pp. 925-933
Citations number
49
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
298
Issue
3
Year of publication
2001
Pages
925 - 933
Database
ISI
SICI code
0022-3565(200109)298:3<925:DSOMNT>2.0.ZU;2-H
Abstract
Disturbance in phosphorylation/dephosphorylation can trigger apoptosis. Lit tle is known as to its effects on mesencephalic dopamine neurons, the major neurons lost in Parkinson's disease. In this study, okadaic acid (OKA), a phosphatase 1 and 2A inhibitor, with greater potency toward 2A, was toxic t o mesencephalic dopamine and gamma -aminobutyric acid (GABA) neurons, howev er, dopamine neurons were 4-fold more sensitive. The EC50 for dopamine vers us GABA toxicity was 1.5 versus 6.5 nM, respectively, and was consistent wi th an inhibition of phosphatase 2A. Dopamine neurons were also more sensiti ve to calyculin-A, a phosphatase inhibitor equipotent toward 1 and 2A. OKA- methyl-ester, which lacks phosphatase inhibitory activity, was without effe ct. DNA laddering typical of apoptosis was observed in cultures at a concen tration that was specifically toxic to dopamine neurons (5 nM). In contrast to the sensitivity of mesencephalic neurons to phosphatase inhibition, inh ibition of protein kinase activity with staurosporine or K252a showed littl e toxicity and protected neurons from OKA. Consistent with in vitro finding s, infusion of 32 to 320 pmol of OKA into the left striatum of rats caused a dose-dependent loss of striatal dopamine without any loss of GABA 1 week following infusion. Acutely, OKA increased tyrosine hydroxylase activity, a phosphatase 2A substrate, and increased dopamine turnover. The above-menti oned findings demonstrate that dysregulation of phosphatase activity is det rimental to mesencephalic neurons, with dopamine neurons, in vitro and in v ivo, being relatively more sensitive to phosphatase 2A inhibition. Disturba nces in the phosphorylation control of proteins unique to dopamine neurons may contribute to their enhanced vulnerability to OKA exposure.