title: PKC epsilon-dependent calcium oscillations associated with metabotropic glutamate receptor 5 prevent agonist-mediated receptor desensitization in astrocytes.
abstract: A critical role has been assigned to protein kinase C (PKC)ε in the control of intracellular calcium oscillations triggered upon activation of type 5 metabotropic glutamate receptor (mGluR5) in cultured astrocytes. Nevertheless, the physiological significance of this particular signalling profile in the response of astrocytes to glutamate remains largely unknown. Considering that kinases are frequently involved in the regulation of G protein-coupled receptors, we have examined a putative link between the nature of the calcium signals and the response regulation upon repeated exposures of astrocytes to the agonist (S)-3,5-dihydroxyphenylglycine. We show that upon repeated mGluR5 activations, a robust desensitization was observed in astrocytes grown in culture conditions favouring the peak-plateau-type response. At variance, in cell cultures where calcium oscillations were predominating, the response was fully preserved even during repeated challenges with the agonist. Pharmacological inhibition of PKCε or genetic suppression of this isoform using shRNA was found to convert an oscillatory calcium profile to a sustained calcium mobilization and this latter profile was subject to desensitization upon repetitive mGluR5 activation. Our results suggest a yet undocumented scheme in which the activity of PKCε contributes to preserve the receptor sensitivity upon repeated or sustained activations. Cover Image for this issue: doi: 10.1111/jnc.13797.
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, Avenue Hippocrate B1.54.10, Brussels, Belgium.
authors.forename: Maxime
authors.initials: M
authors.lastname: Vergouts
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, Avenue Hippocrate B1.54.10, Brussels, Belgium.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Doyen
authors.affiliation: Laboratory of virology, De Duve Institute, Université catholique de Louvain, Avenue Hippocrate B1.74.07, Brussels, Belgium.
authors.forename: Michael
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Université catholique de Louvain, Avenue Mounier B1.53.02, Brussels, Belgium.
authors.forename: Remi
authors.initials: R
authors.lastname: Opsomer
authors.affiliation: Laboratory of virology, De Duve Institute, Université catholique de Louvain, Avenue Hippocrate B1.74.07, Brussels, Belgium.
authors.forename: Thomas
authors.identifier: 0000-0001-9615-8053
authors.initials: T
authors.lastname: Michiels
authors.affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, Avenue Hippocrate B1.54.10, Brussels, Belgium.
authors.forename: Emmanuel
authors.identifier: 0000-0002-8589-3279
authors.initials: E
authors.lastname: Hermans
mesh_terms: D000473:Alkanes / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D003521:Cyclopropanes / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D061251:Primary Cell Culture; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists* / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D000473:Alkanes; D003521:Cyclopropanes; C477949:FR236924; D005904:Glial Fibrillary Acidic Protein; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D008734:Methoxyhydroxyphenylglycol; D051744:Protein Kinase C-epsilon; C010117:3,4-dihydroxyphenylglycol
keywords: Astrocytes; desensitization; glial cells; glutamate; mGluR5; single-cell imaging