Antagonists of protein kinase C inhibit rat retinal glutamate transport activity in situ

Natalie D. Bull, Nigel L. Barnett

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

Abstract

Neuronal and glial high-affinity transporters regulate extracellular glutamate concentration, thereby terminating synaptic transmission and preventing neuronal excitotoxicity. Glutamate transporter activity has been shown to be modulated by protein kinase C (PKC) in cell culture. This is the first study to demonstrate such modulation in situ, by following the fate of the non-metabolisable glutamate transporter substrate, o-aspartate. In the rat retina, pan-isoform PKC inhibition with chelerythrine suppressed glutamate uptake by GLAST (glutamate/aspartate transporter), the dominant excitatory amino acid transporter localized to the glial Müller cells. This effect was mimicked by rottlerin but not by Gö6976, suggesting the involvement of the PKCδ, PKGα, β or γ. Western blotting and immunohistochemical labeling revealed that the suppression of glutamate transport was not due to a change in transporter expression. Inhibition of PKC5 selectively suppressed GLAST but not neuronal glutamate transporter activity. These data suggest that the targeting of specific 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. glaucoma and amyotrophic lateral sclerosis.

Original languageEnglish
Pages (from-to)472-480
Number of pages9
JournalJournal of Neurochemistry
Volume81
Issue number3
DOIs
Publication statusPublished - 5 Aug 2002
Externally publishedYes

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Amino Acid Transport System X-AG
Protein Kinase C
Rats
Glutamic Acid
Neuroglia
Protein Isoforms
Amino Acid Transport Systems
Excitatory Amino Acids
Amyotrophic Lateral Sclerosis
Cell culture
Aspartic Acid
Synaptic Transmission
Glaucoma
Labeling
Modulators
Retina
Homeostasis
Cell Culture Techniques
Western Blotting
Modulation

Cite this

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abstract = "Neuronal and glial high-affinity transporters regulate extracellular glutamate concentration, thereby terminating synaptic transmission and preventing neuronal excitotoxicity. Glutamate transporter activity has been shown to be modulated by protein kinase C (PKC) in cell culture. This is the first study to demonstrate such modulation in situ, by following the fate of the non-metabolisable glutamate transporter substrate, o-aspartate. In the rat retina, pan-isoform PKC inhibition with chelerythrine suppressed glutamate uptake by GLAST (glutamate/aspartate transporter), the dominant excitatory amino acid transporter localized to the glial M{\"u}ller cells. This effect was mimicked by rottlerin but not by G{\"o}6976, suggesting the involvement of the PKCδ, PKGα, β or γ. Western blotting and immunohistochemical labeling revealed that the suppression of glutamate transport was not due to a change in transporter expression. Inhibition of PKC5 selectively suppressed GLAST but not neuronal glutamate transporter activity. These data suggest that the targeting of specific 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. glaucoma and amyotrophic lateral sclerosis.",
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Antagonists of protein kinase C inhibit rat retinal glutamate transport activity in situ. / Bull, Natalie D.; Barnett, Nigel L.

In: Journal of Neurochemistry, Vol. 81, No. 3, 05.08.2002, p. 472-480.

Research output: Contribution to journalArticleResearchpeer-review

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