PERK regulates Gq protein-coupled intracellular Ca2+ dynamics in primary cortical neurons

Abstract

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 Ca²⁺ dynamics in insulin-secreting β-cells underlying glucose-stimulated insulin secretion, and modulates Ca²⁺ signals-dependent working memory, we explored the role of PERK in regulating G_q protein-coupled Ca²⁺ dynamics in pyramidal neurons. We found that acute PERK inhibition by the use of a highly specific PERK inhibitor reduced the intracellular Ca²⁺ rise stimulated by the activation of acetylcholine, metabotropic glutamate and bradykinin-2 receptors in primary cortical neurons. More specifically, acute PERK inhibition increased IP₃ receptor mediated ER Ca²⁺ release, but decreased receptor-operated extracellular Ca²⁺ influx. Impaired G_q protein-coupled intracellular Ca²⁺ 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 Ca²⁺ dynamics in cortical pyramidal neurons.

Keywords: Ca2+; Gq protein-coupled receptor; PERK; Receptor-operated Ca2+ entry.