Effects of methylmercury on protein kinase A and protein kinase C in the mouse brain.
The effects of methylmercury administration on adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (protein kinase A) and protein kinase C were investigated by determining their second messenger bindings ([3H]cAMP binding for protein kinase A and [3H]PDBu for protein kinase C) and enzymatic activities in the brains of methylmercury-treated mice. After single administrations of methylmercury (10 mgHg/kg, sc), no neurological symptoms were observed, while the mercury concentration in the brain reached 5.6 ppm. Neither second messenger bindings nor enzymatic activities of either protein kinase displayed significant changes. When methylmercury was administered repeatedly (10 mg Hg/kg x 5), the mercury concentration was 11.7 ppm and the enzymatic activity of protein kinase C was reduced to 75% of the control level without significant change in [3H]PDBu binding. Significant change has not been observed in either [3H]cAMP binding or enzymatic activity of protein kinase A. The reduction of enzymatic activity of protein kinase C was reversed by the simultaneous administration of selenite (0.5 mgSe/kg x 5). However, the fact that selenite administration alone displayed not a significant but about a 20% increase in [3H]PDBu binding suggested that selenite itself could affect the level of protein kinase C despite having no apparent effects on protein kinase C in vitro. Further investigation is necessary to assess whether protein kinase C is involved in the detoxication mechanism of selenite with respect to methylmercury. Since the mercury concentration in the brain was higher than the IC50s for both protein kinase A and protein kinase C observed in vitro even after single administration, methylmercury might inhibit both protein kinases, which might impair intracellular signal transduction. This might in part conceal the symptoms during the early stages of methylmercury toxicity.
Saijoh
K
K
Department of Public Health, Kobe University School of Medicine, Japan.
Fukunaga
T
T
Katsuyama
H
H
Lee
M J
MJ
Sumino
K
K
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008767:Methylmercury Compounds / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects; D018038:Sodium Selenite / Q000008:administration & dosage
D008767:Methylmercury Compounds; D015240:Phorbol 12,13-Dibutyrate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D018038:Sodium Selenite