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M. Huemmeke, B. Merkl, Y. Koç, S. Dell, A.M. Joussen, M. Plomann; Redistribution of Proteins Involved in Glutamate Receptor Regulation in Diabetic Retina . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4232.
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To analyze the expression and intracellular localization of proteins involved in the regulation of the glutamate receptor transport in the diabetic retinopathy (DR). The regulation of extracellular glutamate levels is a prerequisite for the prevention of excitotoxic neuronal damage dependent on both, sufficient functional glutamate receptors and transporters in synaptic membranes. The PDZ protein PICK1 controls clustering and internalization of its target molecules (e.g. GluR2) and the PKC–PICK1 complex directly controls the surface expression levels of the GluR2 glutamate receptor.
We used the streptozotocin (STZ) rat model of short–term DR to investigate early changes of the DR. Immunohistochemical analysis and subcellular fractionation experiments were made from streptozotocin (STZ)–induced rats of 2 (DM2, n=11) and 6 (DM6, n=12) weeks duration of diabetes mellitus (DM) and compared to a control group in the same age (n=8, respectively).
Immunohistochemical analysis of the retina of DM2 animals revealed changes in the distribution of the PICK1–binding protein PACSIN 1. It appears to be removed from the synaptic contacts in the outer plexiform layer and is retained in cell bodies of neurons within the inner nuclear layer. In the retina of DM2 and DM6 animals PACSIN 1 accumulates in photoreceptor cells close to the outer limiting membrane. These findings are accompanied by corresponding changes of active PKC localization. A similar relocalization was observed for phosphorylated GluR2 representing the pool of internalized AMPA receptors residing in vesicles.
Since both, PACSIN 1 and PKC, are present in complexes containing PICK1 and AMPA receptor chains (like GluR2) we propose that trafficking abnormalities of glutamate receptors and transporters are a prerequisite for excitotoxicity observed in diabetic retinopathy. Further experiments are needed to verify the observed redistributions by subcellular fractionation experiments.
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