In the CNS, high-affinity transporters regulate the extracellular glutamate concentration, thereby terminating excitatory synaptic transmission and preventing neuronal excitotoxicity. Autoradiographic and immunohistochemical studies indicate that the radial glial Muller cells dominate glutamate transport in the retina, utilising GLAST (GLutamate/ ASpartate Transporter). Furthermore, recent studies have shown that GLAST activity is more susceptible to ischaemic attack than the other retinal glutamate transporters - its failure contributing to the dangerous elevation of extracellular glutamate. Glutamate transporter activity has been shown to be modulated by protein kinase C (PKC) in cell culture. We investigated whether PKC could modulate retinal Muller cell glutamate uptake activity in intact retina by following the fate of the non-metabolisable glutamate transporter substrate, D-aspartate, by immunohistochemistry. In the rat retina, pan-isoforrn PKC inhibition with chelerythrine suppressed Muller cell glutamate uptake by GLAST. This effect was mimicked by rottlerin but not by Gii6976, suggesting the involvement of the PKC-delta isoforrn, but not PKC-alpha, beta or gamma. Western blotting and immunohistochemical labelling revealed that the suppression of glutamate transport was not due to a change in transporter expression. Inhibition of PKC-delta selectively suppressed GLAST but not neuronal glutamate transporter activity. These data suggest that the targeting of specific glial glutamate transporters with isoform-specific modulators of PKC activity may have significant implications for the understanding of neurodegenerative conditions arising from compromised glutamate homeostasis, e.g. ischaemia, glaucoma and amyotrophic lateral sclerosis.
|Number of pages||2|
|Publication status||Published - May 2002|
|Event||Fifth European Meeting on Glial Cell Function in Health and Disease - Rome, Italy|
Duration: 21 May 2002 → 25 May 2002
Conference number: 5th
Barnett, NL., & Bull, ND. (2002). Inhibitors of protein kinase C modulate the activity of the Muller cell glutamate transporter GLAS, in the rat retina. Glia, 38(S1), S56-S57. [P203]. https://doi.org/10.1002/glia.6003