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Paquet-Durand, F.* ; Hauck, S.M. ; van Veen, T.* ; Ueffing, M. ; Ekström, P.*

PKG activity causes photoreceptor cell death in two retinitis pigmentosa models.

J. Neurochem. 108, 796-810 (2009)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
Photoreceptor degeneration in retinitis pigmentosa is one of the leading causes of hereditary blindness in the developed world. Although causative genetic mutations have been elucidated in many cases, the underlying neuronal degeneration mechanisms are still unknown. Here, we show that activation of cGMP-dependent protein kinase (PKG) hallmarks photoreceptor degeneration in rd1 and rd2 human homologous mouse models. When induced in wild-type retinae, PKG activity was both necessary and sufficient to trigger cGMP-mediated photoreceptor cell death. Target-specific, pharmacological inhibition of PKG activity in both rd1 and rd2 retinae strongly reduced photoreceptor cell death in organotypic retinal explants. Likewise, inhibition of PKG in vivo, using three different application paradigms, resulted in robust photoreceptor protection in the rd1 retina. These findings suggest a pivotal role for PKG activity in cGMP-mediated photoreceptor degeneration mechanisms and highlight the importance of PKG as a novel target for the pharmacological intervention in RP.
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Publication type Article: Journal article
Document type Scientific Article
Keywords calcium; cGK; cGMP; nitric oxide; rd1 mouse; retina; dependent protein-kinase; vasodilator-stimulated phosphoprotein; inherited retinal degenerations; rod cgmp-phosphodiesterase; nucleotide-gated channels; d-cis-diltiazem; cyclic-gmp; mouse retina; rd mouse; guanosine-monophosphate
ISSN (print) / ISBN 0022-3042
e-ISSN 1471-4159
Quellenangaben Volume: 108, Issue: 3, Pages: 796-810 Article Number: , Supplement: ,
Publisher Wiley
Reviewing status Peer reviewed