PERK regulates G protein-coupled intracellular Ca dynamics in primary cortical neurons.
Siying Zhu, Barbara C McGrath, Yuting Bai, Xin Tang, Douglas R Cavener
Author Information
Siying Zhu: Department of Biology, Center of Cellular Dynamics, the Pennsylvania State University, University Park, PA, 16802, USA.
Barbara C McGrath: Department of Biology, Center of Cellular Dynamics, the Pennsylvania State University, University Park, PA, 16802, USA.
Yuting Bai: Department of Biology, Center of Cellular Dynamics, the Pennsylvania State University, University Park, PA, 16802, USA.
Xin Tang: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA.
Douglas R Cavener: Department of Biology, Center of Cellular Dynamics, the Pennsylvania State University, University Park, PA, 16802, USA. drc9@psu.edu.
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 dynamics in insulin-secreting β-cells underlying glucose-stimulated insulin secretion, and modulates Ca signals-dependent working memory, we explored the role of PERK in regulating G protein-coupled Ca dynamics in pyramidal neurons. We found that acute PERK inhibition by the use of a highly specific PERK inhibitor reduced the intracellular Ca rise stimulated by the activation of acetylcholine, metabotropic glutamate and bradykinin-2 receptors in primary cortical neurons. More specifically, acute PERK inhibition increased IP receptor mediated ER Ca release, but decreased receptor-operated extracellular Ca influx. Impaired G protein-coupled intracellular Ca 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 protein-coupled intracellular Ca dynamics in cortical pyramidal neurons.
