ASIC-vermittelte Regulation des intrazellulären pH in Neuronen des murinen Kortex

The pH-value is regulated very precisely in all mammals to ensure the optimal function of cells and organs. In the central nervous system there are numerous mechanisms to maintain the pH value or, in the event of changes in the pH value, to quickly restore the desired pH optimum. In this work the intracellular pH regeneration in cultured neurons of the murine cortex was investigated and the transporters involved were characterized. The question arose as to whether the transport proteins were influenced by a specific acid treatment (preconditioning). Ischemic preconditioning is a protective mechanism that can protect the cells from a subsequent ischemic event. In some studies, a neuroprotective effect has already been reached by specific preconditioning with acid. In the context of this dissertation it could be shown that previous treatment with acidosis leads to a significant reduction of the expression of the sodium-proton exchanger 1 (NHE1). The mRNA level and also the protein concentration of NHE1 are reduced by preconditioning with acidosis. Regeneration of the intracellular pH after intracellular acidification was altered and transport capacity was reduced. This effect of preconditioning was observed in the neurons of wild type mice, but not in knockout mice lacking a functional ASIC1 gene. The deactivated channel, the Acid Sensing Ion Channel (ASIC), is activated by protons and serves as a mediator for preconditioning.This was the first time that a direct correlation between an acidosis treatment, ASIC1 activity and the NHE1 expression level could be shown. Regeneration of the intracellular pH-value is influenced by the expression of ASIC1 and the activity of ASIC1 and NHE1. This knowledge enables a better understanding of the ASIC channel and offers therapeutic potential to counteract ischemic cell death