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104. Jahrestagung der Deutschen Ophthalmologischen Gesellschaft 2006
Abstract
Abstract
SO.06.07 Changed regulation and localization of Glutamate receptors in diabetic retinopathy Huemmeke M.1,3, Merkl B.2,3, Koç Y.2,3, Dell S.1,3, Joussen A. M.1,3, Plomann M.2,3
1Department of Vitreal Surgery and Center of Molecular Medicine, University hospital of Ophthalmology, Cologne; 2Centers for Biochemistry II, University of Cologne; 3Center of Molecular Medicine, University of Cologne Objective: The aim of this study is 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.
Methods: 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). Advanced disease stage of DR were examined by immunohistochemical analysis of postmortem human retina.
Results: 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. Changes of the GluR distribution could not be observed in these early phases of DR. In comparison to the healthy retina the advanced disease stage of DR leads to an inhomogenous distribution of the phosphorylated GluRs into the different layers of the human retina. These receptors represent the pool of internalized AMPA receptors residing in vesicles. The results are accompanied by corresponding changes of active PKC localization.
Conclusions: 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.
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