FIGURE 2.

Adenosine tone regulates the transmethylation pathway. Pathways in blue reflect steady state pathways, whereas pathways in red show pathway shifts induced by alteration of adenosine homeostasis. Physiological baseline: DNA methylation of cytosine residues is mediated by the transmethylation pathway. S-adenosylmethionine (SAM) donates a methyl group, which is added to cytosine residues by DNMT. In the process SAM is converted to S-adenosylhomocysteine (SAH). SAH is further converted to adenosine (ADO) and homocysteine (HCY) by the enzyme S-adenosylhomocysteine hydrolase. ADO is phosphorylated to AMP by the enzyme adenosine kinase (ADK). HCY is converted to methionine and subsequently back to SAM. DNA methylation is dependent on the constant removal of the obligatory endproducts ADO and HCY. Phase I (epileptogenic trigger): we hypothesize that the injury and/or SE induced decrease of ADK and surge of ADK (Clark et al., 1997; Gouder et al., 2004; Pignataro et al., 2008) shifts the equilibrium constant of the transmethylation pathway to SAH. The increased SAH prevents SAM donation of a methyl group to DNA. Reduced DNA methylation permits the transcription of early epileptogenesis genes. Phase II (epileptogenic condition): increased ADK within reactive astrocytes reduces adenosine tone to pathologically low levels. Low adenosine tone shifts the biochemical pathway to favor SAM conversion to SAH; thereby, DNA methylation will be increased. Pathological hypermethylation of DNA is present in resected hippocampi of mTLE with hippocampal sclerosis patients (Kobow et al., 2009).