title: 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.
authors.affiliation: a Neuroscience Research Center, Shahid Beheshti University of Medical Sciences , Tehran , Iran .
authors.forename: Niloufar
authors.initials: N
authors.lastname: Ansari
authors.forename: Hamid
authors.initials: H
authors.lastname: Hadi-Alijanvand
authors.forename: Marjan
authors.initials: M
authors.lastname: Sabbaghian
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
authors.forename: Fariba
authors.initials: F
authors.lastname: Khodagholi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D003620:Dantrolene / Q000737:chemistry / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C577054:3-thiomethyl-5,6-(dimethoxyphenyl)-1,2,4-triazine; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018696:Neuroprotective Agents; D019837:Ryanodine Receptor Calcium Release Channel; D014227:Triazines; D006861:Hydrogen Peroxide; C109986:2-aminoethoxydiphenyl borate; D003620:Dantrolene; D002118:Calcium
keywords: 2-APB; IP3R; PC12 cells; RyR; apoptosis; autophagy; calcium; dantrolene; endoplasmic reticulum