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S. Kustermann, T. van Veen, W. Raffelsberger, P. Ekström, F. Paquet-Durand; Role of PKA on Photoreceptor Degeneration in the rd1 Mouse Model. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4470.
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PKA, a cAMP dependent protein kinase, is important in activating the transcription factor CREB (cAMP response element-binding protein) which is crucially involved in neuronal survival. Previously it has been demonstrated that in the rd1 mouse, a model for retinal degeneration, retinal CREB is significantly downregulated (Azadi et al., 2006). Furthermore, PKA bears the potential to stabilize ICER (inducible cAMP early repressor) which is the endogenous inhibitor of CREB. To investigate this bivalent role of PKA and the impact of PKA on photoreceptor cell survival we specifically activated or inhibited PKA activity in retinal explants of the rd1 mouse.
Retinas from rd1 mice at postnatal day 5 were cultured in an organotypic culture system for 6 days in total. After 2 days in vitro (DIV) retinal explants were treated for 4 days by adding PKA inhibitor (RP-8-CPT-cAMPS) or activator (SP-8-CPT-cAMPS) to the culture medium. Cell death after treatment was assessed using TUNEL assay and cell death rate was calculated as TUNEL positive cells / µm² of outer nuclear layer (ONL).
After treating retinal explants of rd1 mice for 4 days with a PKA inhibitor we could not observe any significant differences in the number of dying cells within the ONL (3.7 control vs. 3.2 treated) as revealed by TUNEL staining. In an additional set of experiments we could demonstrate that 4 days treatment of retinal explants with a PKA activator showed no significant changes in the amount of dying cells (3.4 control vs. 3.1 treated).
Increased PKA activity as well as PKA inhibition has no apparent impact on photoreceptor cell death in the rd1 mouse model, at least under the short term treatment conditions used here. Further investigations will be needed to demonstrate any potential role of PKA in fine tuning of CREB dependent transcription or on other parameters of the retinal degeneration in the rd1 mouse.
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