title: PERK regulates Gqprotein-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 Gqprotein-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 IP3receptor mediated ER Ca2+release, but decreased receptor-operated extracellular Ca2+influx. Impaired Gqprotein-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 Gqprotein-coupled intracellular Ca2+dynamics in cortical pyramidal neurons.
authors.affiliation: Department of Biology, Center of Cellular Dynamics, the Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Siying
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Biology, Center of Cellular Dynamics, the Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: McGrath
authors.affiliation: Department of Biology, Center of Cellular Dynamics, the Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Biology, Center of Cellular Dynamics, the Pennsylvania State University, University Park, PA, 16802, USA. drc9@psu.edu.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Cavener
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002118:Calcium; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019892:eIF-2 Kinase
keywords: Ca2+; Gq protein-coupled receptor; PERK; Receptor-operated Ca2+ entry