РОЛЬ КОТРАНСМИТЕРОВ В РЕГУЛЯЦИИ ДЕЯТЕЛЬНОСТИ СЕРДЦА КРЫС В ПОСТНАТАЛЬНОМ ОНТОГЕНЕЗЕ

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