Files and links (2)
Published, Version of Record (VoR)Open Access (License Unspecified), Open
Journal article
cGMP Accumulation Causes Photoreceptor Degeneration in CNG Channel Deficiency: Evidence of cGMP Cytotoxicity Independently of Enhanced CNG Channel Function
The Journal of neuroscience, v 33(37), pp 14939-U337
11 Sep 2013
PMID: 24027293
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Photoreceptor cyclic nucleotide-gated (CNG) channels regulate Ca2+ influx in rod and cone photoreceptors. cGMP, the native ligand of the photoreceptor CNG channels, has been associated with cytotoxicity when its levels rise above normal due to defects in photoreceptor phosphodiesterase (PDE6) or regulation of retinal guanylyl cyclase (retGC). We found a massive accumulation of cGMP in CNGA3-deficient retina and investigated whether cGMP accumulation plays a role in cone degeneration in CNG channel deficiency. The time course study showed that the retinal cGMP level in Cnga3(-/-); Nrl(-/-) mice with CNGA3 deficiency on a cone-dominant background was sharply increased at postnatal day 8 (P8), peaked around P10 -P15, remained high through P30 -P60, and returned to near control level at P90. This elevation pattern correlated with photoreceptor apoptotic death, which peaked around P15-P20. In Cnga3(-/-); Gucy2e(-/-) mice lacking retGC1, cone density and expression levels of cone-specific proteins were significantly increased compared with Cnga3(-/-), consistent with a role of cGMP accumulation as the major contributor to cone death caused by CNG channel deficiency. The activity and expression levels of cGMP-dependent protein kinase G (PKG) were significantly increased in Cnga3(-/-); Nrl(-/-) retina compared with Nrl(-/-), suggesting an involvement of PKG regulation in cell death. Our results indicate that cGMP accumulation in photoreceptors can itself exert cytotoxic effect in cones, independently of CNG channel activity and Ca2+ influx.
Metrics
Details
- Title
- cGMP Accumulation Causes Photoreceptor Degeneration in CNG Channel Deficiency: Evidence of cGMP Cytotoxicity Independently of Enhanced CNG Channel Function
- Creators
- Jianhua Xu - University of Oklahoma Health Sciences CenterLynsie Morris - University of Oklahoma Health Sciences CenterArjun Thapa - University of Oklahoma Health Sciences CenterHongwei Ma - University of Oklahoma Health Sciences CenterStylianos Michalakis - Center for Integrated Protein Science MunichMartin Biel - Center for Integrated Protein Science MunichWolfgang Baehr - University of UtahIgor V. Peshenko - Salus UniversityAlexander M. Dizhoor - Salus UniversityXi-Qin Ding - University of Oklahoma Health Sciences Center
- Publication Details
- The Journal of neuroscience, v 33(37), pp 14939-U337
- Publisher
- Soc Neuroscience
- Number of pages
- 11
- Grant note
- Deutsche Forschungsgemeinschaft; German Research Foundation (DFG) P20RR017703 / National Center for Research Resources; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) Oklahoma Center for the Advancement of Science Technology P30EY12190; R01EY019490; R01EY08123; R01EY019298; R01EY011522 / National Eye Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Eye Institute (NEI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Web of Science ID
- WOS:000324316200031
- Scopus ID
- 2-s2.0-84883667424
- Other Identifier
- 991022035257904721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences