Antagonists of protein kinase C inhibit rat retinal glutamate transport activity in situ.
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, d-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 PKCdelta isoform, but not PKCalpha, beta or gamma. Western blotting and immunohistochemical labeling revealed that the suppression of glutamate transport was not due to a change in transporter expression. Inhibition of PKCdelta 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.
Bull
Natalie D
ND
Vision, Touch and Hearing Research Centre, School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
Barnett
Nigel L
NL
D000098:Acetophenones / Q000494:pharmacology; D000470:Alkaloids; D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000493:pharmacokinetics; D053119:Benzophenanthridines; D001578:Benzopyrans / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012160:Retina / Q000166:cytology / Q000378:metabolism*
D000098:Acetophenones; D000470:Alkaloids; D027322:Amino Acid Transport System X-AG; D053119:Benzophenanthridines; D001578:Benzopyrans; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D010617:Phenanthridines; C081021:Go 6976; D001224:Aspartic Acid; D018698:Glutamic Acid; C085746:rottlerin; C016299:chelerythrine; D011493:Protein Kinase C