PERK regulates G(q) protein-coupled intracellular Ca(2+) dynamics in primary cortical neurons

PERK (EIF2AK3) is an ER-resident eIF2α kinase required for behavioral flexibility and metabotropic glutamate receptor-dependent long-term depression via its translational control. Motivated by the recent discoveries that PERK regulates Ca(2+) dynamics in insulin-secreting β-cells underlying glucose-stimulated insulin secretion, and modulates Ca(2+) signals-dependent working memory, we explored the role of PERK in regulating G(q) protein-coupled Ca(2+) dynamics in pyramidal neurons. We found that acute PERK inhibition by the use of a highly specific PERK inhibitor reduced the intracellular Ca(2+) rise stimulated by the activation of acetylcholine, metabotropic glutamate and bradykinin-2 receptors in primary cortical neurons. More specifically, acute PERK inhibition increased IP(3) receptor mediated ER Ca(2+) release, but decreased receptor-operated extracellular Ca(2+) influx. Impaired G(q) protein-coupled intracellular Ca(2+) rise was also observed in genetic Perk knockout neurons. Taken together, our findings reveal a novel role of PERK in neurons, which is eIF2α-independent, and suggest that the impaired working memory in forebrain-specific Perk knockout mice may stem from altered G(q) protein-coupled intracellular Ca(2+) dynamics in cortical pyramidal neurons. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-016-0268-5) contains supplementary material, which is available to authorized users.