6 CONCLUSION

6.1 Novel findings

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The present study was undertaken to investigate the mechanism of modulation of transient potassium channels by arachidonic acid and possible involvement/contribution of free radicals to this process. Based on the presented results, the following novel findings could be briefly summarized as:

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1) The transient potassium current (IA) is extremely sensitive to intracellular arachidonic acid in neurons from acute slices. 1 pM AA was sufficient to reduce A-current by about 50 % in CA1 pyramidal neurons, by ~60 % in ELCIII pyramidal neurons and Kv4.2-transfected HEK293 cells, and by ~70% in ECLII stellate cells and Kv1.4-transfected HEK 293 cells.

2) The effect of AA on the transient potassium currents in ECLII stellate neurons, ECLIII pyramidal neurons and CA1 pyramidal neurons is mimicked by the polyunsaturated fatty acid ETYA. However, ETYA required 100-fold higher concentration. 3) The delayed rectifier current is in general (with exception of ECLII neurons) insensitive to 1 pM arachidonic acid. 4) AA-mediated modulation of IA involves ROS formation, as some of the AA effects are blocked by antioxidants. 5) Existence of more than one modulation sites for arachidonic acid and H2O2 on potassium channel complex molecules is possible. 6) Neurons from the entorhinal cortex (LII and LIII) tend to be more sensitive to oxidative stress than CA1 pyramidal neurons. 7) Both delayed rectifier and transient potassium channels reacted to exogenously applied H2O2 with strong reduction of their conductivity. 8) In contrast to primary cultured neurons, H2O2 effects in acute brain slices were not always abolished by antioxidants, which reveal different mechanisms in current modulation in neurons from acute brain slices compared to neurons in culture. 9) Antioxidants by themselves may affect functionality of potassium channels.

6.2 Significance

The results from this study provided evidence that endogenously generated free radical processes contribute significantly to the regulation of Kv channels in entorhinal cortex and the hippocampus.

6.3 Outlook

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The functional properties of many Kv channels are clearly altered by oxidizing and reducing treatments. How these oxidative modifications contribute to neuron and other cell function needs to be investigated. The results presented in this study, together with the recent findings in the field suggested, that we are just at the beginning of the revolution of the ROS-and O2-signalling research that may shed light not only on normal biological functions of the brain, but on disease mechanisms that are so far poorly understood, as Alzheimer’s, Parkinson’s, schizophrenia, etc. Future research should focus on: 1) discovering molecular, physiological and pharmacological features of missing key elements of the functional channels; 2) their precise cellular and subcellular localization ; 3) biochemical machinery involved in channel modulation; 4) roles played by ROS in channel modulation in various neurological and psychiatric disorders; 5) novel ROS signalling pathways.


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