РОЛЬ КОТРАНСМИТЕРОВ В РЕГУЛЯЦИИ ДЕЯТЕЛЬНОСТИ СЕРДЦА КРЫС В ПОСТНАТАЛЬНОМ ОНТОГЕНЕЗЕ
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НИИ ноpмальной физиологии им. П.К. Анохина
Год издания: 2015
Кол-во страниц: 5
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Manganese is an essential metal for humans and performs a lot of biological functions. However, manganese, at higher doses, is the toxic metal, which can lead to such illnesses as Parkinson’s disease and “manganism”. The molecular mechanisms of manganese-induced toxicity are still unknown. There is the hypothesis according to which the presence of manganese’s overabundance can induce the incorrect incorporation of nucleotides by some DNA-polymerases during the DNAsynthesis [1]. DNA-polymerase ι (Pol ι) is the likely candidate for the role of such enzyme, as Pol ι is the only DNA-polymerase, that is more efficient activated by Mn2+ than by Mg2 and incorporate dG opposite dT [2] . We received the resistance cell line from SKOV-3, which survived in the presence of toxic manganese’s concentration to know if the manganese-induced toxicity relates to activity of Pol ι. As a result the new cell line survives in the presence of 200 mkM Mn2+ whereas the IC50 of SKOV-3 is 80 mkM Mn2+. However the activity of Pol ι in new cell lines is the same as in SKOV-3. We supposed , that the manganese-induced toxicity can be neutralized by poly(ADP-rybose) polymerase (PARP), which is the main enzyme that responses for elimination of DNA breaks. We compared the extent of poly(ADP-ribosyl)ation, which was determined by immunological detection of poly(ADP-rybose), and established that the level of PARP activity is higher in 1.7 times in new cell line than in SKOV-3. Perhaps enzyme PARP delets the DNA-breaks during the DNA-synthesis and allows new cells to survive in the presense of toxic manganese’s concentration. However, PARP superactivity can lead to the impairment of cell functions and induce the caspase-independent programmed cell death Parthanatos [3]. The new resistant cells have really low proliferative rate in comparison with SKOV-3 and PARP inhibition increases their proliferative rate. So according to the received results we sugest the hypothesis that the overabundance of manganese leads to numerous DNA-breaks through activation Pol ι and therefore induces PARP activation led to NAD+ depletion. This fact can be the source of manganese-induced toxicity for cells. СПИСОК ЛИТЕРАТУРЫ 1. Bornhorst J., Ebert F., Hartwig A., Michalke B., Schwerdtle T. (2010) J. Environ. Monit., 12, 2062-2069. 2. Kazakov A.A., Grishina E.E., Tarantul V.Z., Gening L.V. (2010) Biochemistry, 75, 1031-1039. 3. Andrabi, S.A., Kim, N.S., Yu, S.W., Wang, H., Koh, D.W., Sasaki, M., Klaus, J.A., Otsuka,T., Zhang, Z., Koehler, R.C., Hurn, P.D., Poirier, G.G., Dawson, V.L., Dawson, T.M. (2006) Proc.Nattl.Acad.Sci.U.S.A., 103, 18308-18313. DOI:10.12737/12353 РОЛЬ КОТРАНСМИТЕРОВ В РЕГУЛЯЦИИ ДЕЯТЕЛЬНОСТИ СЕРДЦА КРЫС В ПОСТНАТАЛЬНОМ ОНТОГЕНЕЗЕ А.А. Зверев, Т.А. Аникина, А.В. Крылова, Т.Л. Зефиров