Anti-KARS (aa 280-597) polyclonal antibody

The excitotoxicity induced by kainic acid (KA) is thought to contribute to the development of Alzheimer's disease (AD); however, the mechanisms underlying this excitotoxicity remain unknown. In the current study, we investigated the dynamic changes in tau phosphorylation and their associations with the excitotoxicity induced by intraperitoneal injection of KA in the mouse brain. We found that KA-induced excitotoxicity led to sustained hyperphosphorylation of tau in MAPT transgenic (Tg) mice. By using cultured microglia and mouse brains, we showed that KA treatment specifically induced endoplasmic reticulum (ER) stress, which was characterized by activation of the major biomarkers of ER, such as ATF6, GRP78, and IRE1, and resulted in stimulation of inflammasomes. KA receptors (KARs), such as Girk1, were determined to be involved in this KAinduced ER stress. ER stress was also shown to activate inflammasomes by stimulating the expression of the two major components of inflammasomes, nucleotide binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) and nuclear factor (NF)-kappa B, and eventually causing the production of interleukin-1 beta (IL-1 beta). Inhibition of NLRP3 or NF-kappa B by Bay11-7082 resulted in reduction of KA-induced IL-1 beta production. Our results also revealed the positive effects of IL-1 beta on tau phosphorylation, which was blocked by Bay11-7082. Notably, the results indicate that Bay11-7082 acts against KA-induced neuronal degeneration, tau phosphorylation, and memory defects via inflammasomes, which further highlight the protective role of Bay11-7082 in KA-induced neuronal defects.

Kainate receptors (KARs) are tetrameric ionotropic glutamate receptors composed of the combinations of five subunits GluK1-GluK5. KARs are structurally related to AMPA receptors but they serve quite distinct functions by regulating the activity of synaptic circuits at presynaptic and postsynaptic sites, through either ionotropic or metabotropic actions. Although kainate is a potent neurotoxin known to induce acute seizures through activation of KARs, the actual role of KARs in the clinically-relevant chronic phase of temporal lobe epilepsy (TLE) has long been elusive. Recent evidences have described pathophysiological mechanisms of heteromeric GluK2/GluK5 KARs in generating recurrent seizures in chronic epilepsy. The role of the other major subunit GluK1 in epileptogenic activity is still a matter of debate. This review will present the current knowledge on the subtype-specific pharmacology of KARs and highlight recent results linking KARs to epileptic conditions.