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Vol. 16, Art. 95 (pp. 1062-1076)    |    2015       

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Impact of methyl L-methionine , coenzyme NAD+,certain blockers of cation channels and kinase G on hyperactivation of neuronal networks by ammonium ions.

Kononov A.V. 1, Galimova2 M.H., Dynnik V.V.1,2

1Federal State Budget Organization of Science ,Institute of Cell Biophysics RAS, 142290, Pushchino, Russia, Institutskaya 3
2Federal State Budget Organization of Science, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290, Pushchino, Russia, Institutskaya 3

Brief summary

The purpose of the experiments was to investigate the effects of: methyl L-methionine (vitamin U), coenzyme NAD+ and certain cation channel modulators on hyperactivation of neural networks by ammonium ions (NH4+). The experiments were performed on neuroglial cultures of rat hippocampal cells (12-18 DIV) , using fluorescent microscopy and the registration of cellular Ca++ in the neurons and astrocytes. It has been shown, that vitamin U (1-3 mM) and ZD 4456 (20-30 μM), blocker of hyperpolarization-activated cyclic nucleotide dependent cation (HCN) -channels, - both may completely suppress the activity of neural networks accelerated by 6-8 mM NH4Cl. The effect of vitamin U persists in the presence of pertussis toxin (Gi,0 ?proteins inhibitor) and bicuculline (blocker of GABAa receptors). This reveals that vitamin U action is different from the action of other methylamines (betaine, etc). The effect of ZD 4456 may indicate on possible activation of HCN-channels by NH4+, that apparently may contribute to hyperactivation of neuronal networks. NAD+ (1-3 mM), activating various potassium channels, hyperpolarizes the neurons and inhibits spontaneous network activity. Subsequent addition of NH4Cl causes slow rise of baseline (resting) level of Ca++ and of the amplitudes Ca++- oscillations in one group of neurons in the network (30% of all cells) . Full restoration of hyperactivity in this group is observed within 260 ? 280 s and is followed by fast recovery of the activity in the rest of the network (70% of cells), after attaining by these cells of Ca++ threshold level (Cat++). Time shift between both groups of cells disappears in the presence of slow Ca++ -dependent potassium channels (SK) blocker apamin. Restoration of network hyperactivity is observed within 120-130 s, after attaining by all cells of Cat++. In the presence of protein kinase G activator 8-bromo-cGMP, the time shift produced by ammonia is preserved. Network activity is restored within 80- 90 s, but all groups of cells quickly stop firing and about 60% of these cells are moving into the state with high Ca++ level. All these results may indicate on possible implication of HCN- -channels, some Na+ and Ca++-channels and Ca++ -dependent K+ channels in the effects produced by NH4+. Blockade or activation of metabotropic glutamate receptor type 1 (mGLUR1,5) and inhibition of lipid kinase (PI3K) does not affect the effect of ammonium ions. The results obtained may allow to find out the mechanisms of toxic action of NH4+ and develop new methods of pharmacological correction of hyperammonemia.


Key words

neural networks, ammonium ion, vitamin U , HCN and SK- channels, protein kinase G, hyperammonemia.

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