Interaction of 2-APB, dantrolene, and TDMT with IP3R and RyR modulates ER stress-induced programmed cell death I and II in neuron-like PC12 cells: an experimental and computational investigation

Abstract

Ca(2+) is an essential second messenger, playing a fundamental role in maintaining cell viability and neuronal activity. Two specific endoplasmic reticulum calcium channels, ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs) play an important role in Ca(2+) regulation. In the present study, we provided a 3D structure of RyR and IP3R by homology modeling, and we predicted their interactions with a known neuroprotective compound, 3-thiomethyl-5,6-(dimethoxyphenyl)-1,2,4-triazine (TDMT), as well as two inhibitors, dantrolene and 2-aminoethoxydiphenyl borate (2-APB). Interestingly, we found that dantrolene and 2-APB can bind to the IP3-binding domain of IP3R and RyR, while TDMT may directly block both channels by interacting with the putative resident domains in the pore. Cell culture experiments showed that these compounds could protect PC12 cells against H2O2-induced apoptosis and activate autophagic pathways. Collectively, our computational (in silico) and cell culture studies suggest that RyR and IP3R are novel and promising targets to be used against neurodegenerative diseases.

Ryanodine‐sensitive intracellular Ca2+ channels are involved in the output from the SCN circadian clock

“…Although dantrolene is an inhibitor of RyR 2 (Dulhunty et al ., ), a portion of the neurons, which had very low levels of basal [Ca 2+ ] i , responded with an increase in cytoplasmic [Ca 2+ ] i after adding 10 μ m dantrolene. We hypothesize that this discrepancy could be attributed to Ca 2+ release via IP 3 R Ca 2+ channels, which may be activated when the [Ca 2+ ] i is very low and RyR are blocked, as part of a homeostatic calcium control mechanism (Parys & De Smedt, ; Ansari et al ., ).…”

Current data regarding the structure-toxicity relationship of boron-containing compounds

“…Though only a few studies on the toxicity of boron go beyond boric and boronic acids, it is known that some boroles (Fan, 2010), boranes (Ruhaak, 2010;Crowe, 2015), borinic acids (Ansari, 2014;Soriano-Ursúa, 2014b) and BODIPY derivatives (Alford;) are considered quite poisonous compared to structurally related boron-free compounds (Duydu, 2015). On the other hand, these BCCs are probably advantageous agents for diagnosis and therapeutics.…”

Chronic exposure to cerebrospinal fluid of multiple system atrophy in neuroblastoma and glioblastoma cells induces cytotoxicity via ER stress and autophagy activation

“…The understanding of the complex relationship between ER stress, autophagy and apoptosis has not been clarified until now. Previous studies demonstrated that ER stress regulates the apoptotic cell death and autophagic cell death [ 46 , 65 ]. When the cells expose to a mild stress, mild ER stress promotes neuroprotection via the activation of autophagy [ 46 , 65 ].…”