title: Calcium mobilization by ryanodine promotes the phosphorylation of initiation factor 2alpha subunit and inhibits protein synthesis in cultured neurons.
abstract: Protein synthesis plays an important role in the viability and function of the cell. There is evidence indicating that Ca2+ may be a physiological regulator of the translational process. In the present study, the effect of agents that increase intracellular calcium levels by different mechanisms, as well as repercussion on the rate of protein synthesis, including phosphorylation of initiation factor 2alpha subunit, and double-stranded RNA-dependent eIF-2alpha kinase (PKR) activity were analyzed. Glutamate (100 microM) and K+ (60 mM), which increase intracellular calcium levels (the former mostly by the influx of extracellular calcium via voltage-sensitive calcium channels, and the latter by receptor-operated calcium channels), and carbachol (1 mM), as well as glutamate, which mobilizes intracellular calcium from the endoplasmic reticulum via activation of inositol 1,4,5-trisphosphate receptor, did not modify any of the analyzed parameters. Nevertheless, 100 nM ryanodine, which increases intracellular calcium concentration by activating the ryanodine receptor, promoted a significant decrease in the rate of protein synthesis and increased both initiation factor 2alpha subunit phosphorylation and PKR activity. From our results, we can conclude that inhibition of protein synthesis is dependent on the mobilization of intracellular calcium from internal stores. Moreover, they strongly suggest that this inhibition is only promoted when calcium is increased via ryanodine receptor, and possibly by activation of PKR activity.
authors.affiliation: Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Alcázar
authors.forename: C
authors.initials: C
authors.lastname: Martín de la Vega
authors.forename: E
authors.initials: E
authors.lastname: Bazán
authors.forename: J L
authors.initials: JL
authors.lastname: Fando
authors.forename: M
authors.initials: M
authors.lastname: Salinas
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D007425:Intracellular Membranes / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D039881:Prokaryotic Initiation Factor-2; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D051381:Rats; D012433:Ryanodine / Q000494:pharmacology*
chemical_list: D010448:Peptide Initiation Factors; D039881:Prokaryotic Initiation Factor-2; D011500:Protein Synthesis Inhibitors; D012433:Ryanodine; D002118:Calcium