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 Gq 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 Gq 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 Gq protein-coupled intracellular Ca2+ dynamics in cortical pyramidal neurons.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0268-5) contains supplementary material, which is available to authorized users.
Highlights
Calcium (Ca2+) serves as an important second messenger in the central nervous system, as it regulates various neuronal processes including neurotransmitter release, synaptic plasticity, neuron excitability, and neuronal gene transcription [1]
In pyramidal neurons, Gq protein-coupled intracellular Ca2+ rise induced by muscarinic acetylcholine receptors (mAChR) or Group 1 metabotropic glutamate receptor (mGluR1) activation is required for the induction of Ca2+-activated nonselective cationic current (ICAN) [4, 5], which is considered the ionic mechanism underlying persistent neuronal firing essential for working memory
Acute PERK inhibition impairs Gq protein-coupled intracellular Ca2+ rise in primary cortical neurons To acutely inhibit PERK enzyme activity in primary cortical neurons, we took advantage of a highly specific inhibitor of PERK, GSK2606414 (PERKi), which acts by competing for the ATP binding domain in the catalytic site [11]
Summary
Calcium (Ca2+) serves as an important second messenger in the central nervous system, as it regulates various neuronal processes including neurotransmitter release, synaptic plasticity, neuron excitability, and neuronal gene transcription [1]. Initiators of intracellular Ca2+ rise in neurons include the Gq-protein coupled receptors, whose activation upon agonist binding leads to the activation of Gq/phospholipase C (PLC) pathway. While the increased cytosol IP3 induces internal Ca2+ release by binding with ER resident inositol-1,4,5-triphosphate receptor (IP3R), the activation of Gq/PLC cascade further stimulates receptor-operated Ca2+ influx from external space. The central nervous system expresses a variety of Gq protein-coupled receptors including the M1 and M3 muscarinic acetylcholine receptors (mAChR), the group. In pyramidal neurons, Gq protein-coupled intracellular Ca2+ rise induced by mAChR or mGluR1 activation is required for the induction of Ca2+-activated nonselective cationic current (ICAN) [4, 5], which is considered the ionic mechanism underlying persistent neuronal firing essential for working memory.
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