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Constitutive downregulation protein kinase C epsilon in hSOD1 G93A astrocytes influences mGluR5 signaling and the regulation of glutamate uptake
Author(s) -
Vergouts Maxime,
Doyen Pierre J,
Peeters Michael,
Opsomer Remi,
Hermans Emmanuel
Publication year - 2018
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23279
Subject(s) - metabotropic glutamate receptor 5 , glutamate receptor , astrocyte , protein kinase c , biology , metabotropic glutamate receptor , microbiology and biotechnology , neuroprotection , excitotoxicity , downregulation and upregulation , kinase , neuroscience , biochemistry , receptor , central nervous system , gene
Accumulating evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a non‐cell‐autonomous process and that impaired glutamate clearance by astrocytes, leading to excitotoxicity, could participate in progression of the disease. In astrocytes derived from an animal model of ALS (hSOD1 G93A rats), activation of type 5 metabotropic glutamate receptor (mGluR5) fails to increase glutamate uptake, impeding a putative dynamic neuroprotective mechanism involving astrocytes. Using astrocyte cultures from hSOD1 G93A rats, we have demonstrated that the typical Ca 2+ oscillations associated with mGluR5 activation were reduced, and that the majority of cells responded with a sustained elevation of intracellular Ca 2+ concentration. Since the expression of protein kinase C epsilon isoform (PKCɛ) has been found to be considerably reduced in astrocytes from hSOD1 G93A rats, the consequences of manipulating its activity and expression on mGluR5 signaling and on the regulation of glutamate uptake have been examined. Increasing PKCɛ expression was found to restore Ca 2+ oscillations induced by mGluR5 activation in hSOD1 G93A ‐expressing astrocytes. This was also associated with an increase in glutamate uptake capacity in response to mGluR5 activation. Conversely, reducing PKCɛ expression in astrocytes from wild‐type animals with specific PKCɛ‐shRNAs was found to alter the mGluR5 associated oscillatory signaling profile, and consistently reduced the regulation of the glutamate uptake‐mediated by mGluR5 activation. These results suggest that PKCɛ is required to generate Ca 2+ oscillations following mGluR5 activation, which support the regulation of astrocytic glutamate uptake. Reduced expression of astrocytic PKCɛ could impair this neuroprotective process and participate in the progression of ALS.