Olanzapine In summary EP signaling modulates heteromeric kai
In summary, EP1 signaling modulates heteromeric kainate receptors at multiple steps, both sensitizing mice to kainate-evoked status epilepticus and, separately, exacerbating the downstream consequences of status epilepticus. These results, together with those of Serrano et al. (2011) and Jiang et al. (2013), suggest that activation of both EP1 and EP2 receptors by COX-2 derived PGE2 contributes to neuropathology after status epilepticus in mice. Heteromeric kainate receptors consisting of GluK2 and a high affinity kainate receptor subunit (GluK4 or GluK5) are potentiated by activation of EP1 receptors in a PKC dependent manner, likely via Olanzapine of critical residues located in the membrane-proximal C-terminus of GluK4 or GluK5. The regulation described here confers distinct functional properties to heteromeric kainate receptors that may serve as a convergent molecular basis for kainate receptor and prostanoid receptor cross-talk. Such cross-talk between ionotropic glutamate receptors and the prostanoid receptors may create novel therapeutic opportunities. Although the roles of prostanoid receptors in temporal lobe epilepsy have not been fully addressed, selective EP1 receptor inhibitors could prove useful as a therapeutic strategy for status epilepticus and associated neuropathologies, as well as for other disorders dependent on kainate receptor activation, such as neuropathic pain. Alternatively, given the similarities in effects of EP1 ablation and EP2 antagonism, it could be worthwhile to develop inhibitors of the PTGES prostaglandin synthase.
Acknowledgments This work is supported by NIHRO1 NS036604, U01 NS058158 (RD), P20 NS080185 and T32 DA15040 (AR), and in part by the neuronal imaging core facilities grant P30 NS055077. Participated in research design: Rojas and Dingledine. Conducted experiments: Rojas, Gueorguieva, Quan, Lelutiu and Shaw. Performed data analysis: Rojas, Gueorguieva, Quan and Dingledine. Wrote or contributed to the writing of the manuscript: Rojas and Dingledine
Introduction Curcumin, a poly phenolic compound isolated from turmeric, has been demonstrated to have various pharmacological activities ranging from anti-inflammatory, anti-cancer, anti-oxidant effects to anti-atherosclerotic, anti-microbial, and wound healing actions (Kunnumakkara et al., 2016). Importantly, in recent years, curcumin has been shown to have beneficial effects in alleviating cognitive deficits in neurodegenereative disorders such as Alzheimer\'s and Parkinson\'s diseases (Ji and Shen, 2014, Goozee et al., 2016, Kunnumakkara et al., 2016). Although therapeutic effects of curcumin on several pathological conditions and animal disease models have been well documented, the molecular mechanism of curcumin effects in cells are poorly understood. These diverse pharmacological activities of curcumin are based on its chemical features and complex molecular structure, as well as its ability to interact with multiple signaling molecules (Zhang et al., 2014). To date, several membrane proteins including protein kinases, enzymes, transporters and ion channels have been identified as targets of curcumin (Zhang et al., 2014, Kunnumakkara et al., 2016). Nicotinic acetylcholine (nACh) receptors are important members of the ligand-gated ion channel family that includes GABAA, glycine, and 5-HT3 receptors. The homomeric α7 nACh receptor subtype is abundantly expressed in the central nervous system and periphery and plays a key role in synaptic plasticity and disease (Albuquerque et al., 2009). Neuronal α7-nACh receptors are recognized targets for drug development in several pre-clinical models of neuro-degenerative disorders including Alzheimer\'s disease (Thomsen et al., 2010). In the present study, we have investigated the effects of curcumin on human α7-nACh receptors expressed in SH-EP1 cells. We provide novel evidence that curcumin potentiates intracellular Ca2+ transients of the ligand-gated α7-nACh receptors.