Frontier of epilepsy research - mTOR signaling pathway

Abstract

Studies of epilepsy have mainly focused on the membrane proteins that control neuronal excitability. Recently, attention has been shifting to intracellular proteins and their interactions, signaling cascades and feedback regulation as they relate to epilepsy. The mTOR (mammalian target of rapamycin) signal transduction pathway, especially, has been suggested to play an important role in this regard. These pathways are involved in major physiological processes as well as in numerous pathological conditions. Here, involvement of the mTOR pathway in epilepsy will be reviewed by presenting; an overview of the pathway, a brief description of key signaling molecules, a summary of independent reports and possible implications of abnormalities of those molecules in epilepsy, a discussion of the lack of experimental data, and questions raised for the understanding its epileptogenic mechanism.

Figure 1

Overview of mTOR signaling pathway. Activation and inhibition of signaling molecules by phosphorylation are shown in red and blue respectively.

Figure 2

Genetic mutations of signaling molecules implicated in mTOR pathway (red Xs). Red arrows (up- or downward) indicate the changes in activity of particular molecules in epileptic conditions. Causatives for acquired epilepsy are described in gray. Therapeutic intervening possibilities are shown in boxes. NT - neurotransmitter receptor.

Figure 3

Signaling molecules implicated in epilepsy (see the text for the detail). Arrows indicate the phosphorylation events. Up- and downward arrows indicate the changes in the expression level or activity of particular molecules. Double arrows indicate the protein-protein interaction. Some interactions were induced by phosphorylation. (A) PIM-1 is increased in kainate model. (B) 14-3-3 interacts with BID and dissociates from BAD in kainate model. (C) HSP70 level is increased in kainate model. (D) AKT decreased BIM expression in epilepsy model. AKT is activated by PDK1 phosphorylation at T308 and mTORC2 phosphorylation at S473. AKT modulates molecules involved in apoptosiss and cell cyle as well as other molecules in the mTOR pathway. (E) Various protein-protein interactions with TSC1 and TSC2. When mutated, TSC1/2 lose control of Rheb activity. (F) AMPK and CaMKKβ are increased in kainate model, causing TSC2 inhibition. STRADα in an epileptic condition was indicated in red. AMPK is phosphorylated at T172 by STRADα-MO25α-LKB1 complex. (G) GSK3β is inhibited by phosphorylation at S9. In lafora disease, GSK3β can not be regulated due to the mutation in laforin, a phosphatase. (H) Activation of ERK decrease the surface expression of Kv4.2 channels in kainate model. KA - kainic acid, T-Threonine, S-Serine.