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

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 Ca²⁺ oscillations associated with mGluR5 activation were reduced, and that the majority of cells responded with a sustained elevation of intracellular Ca²⁺ concentration. Since the expression of protein kinase C epsilon isoform 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 expression was found to restore Ca²⁺ 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 duanyu1531ɛ expression in astrocytes from wild-type animals with specific 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 duanyu1531ɛ is required to generate Ca²⁺ oscillations following mGluR5 activation, which support the regulation of astrocytic glutamate uptake. Reduced expression of astrocytic duanyu1531ɛ could impair this neuroprotective process and participate in the progression of ALS.

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