Constitutive downregulation protein kinase C epsilon in hSOD1^G93A astrocytes influences mGluR5 signaling and the regulation of glutamate uptake

Dec 22, 2017Glia

Lower levels of protein kinase C epsilon in mutant astrocytes affect glutamate receptor signals and glutamate absorption

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Abstract

Activation of type 5 metabotropic glutamate receptor (mGluR5) in astrocytes from a model of ALS shows impaired glutamate uptake and altered calcium signaling.

Impaired glutamate clearance by astrocytes may contribute to motor neuron degeneration in ALS.
Astrocytes from hSOD1 rats exhibit reduced calcium oscillations upon mGluR5 activation.
Increased expression of protein kinase C epsilon isoform (PKCɛ) restores calcium oscillations and enhances glutamate uptake in hSOD1 astrocytes.
Reduced PKCɛ expression alters calcium signaling and decreases glutamate uptake in astrocytes from wild-type animals.
Lower levels of astrocytic PKCɛ could affect neuroprotective mechanisms and may play a role in ALS progression.

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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 (hSOD1rats), 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 hSOD1rats, we have demonstrated that the typical Caoscillations associated with mGluR5 activation were reduced, and that the majority of cells responded with a sustained elevation of intracellular Caconcentration. Since the expression of protein kinase C epsilon isoform (PKCɛ) has been found to be considerably reduced in astrocytes from hSOD1rats, 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 Caoscillations induced by mGluR5 activation in hSOD1-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 Caoscillations 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. G93A G93A2+ 2+ G93A2+ G93A2+

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Constitutive downregulation protein kinase C epsilon in hSOD1^G93A astrocytes influences mGluR5 signaling and the regulation of glutamate uptake

Abstract

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