title: cGMP accumulation causes photoreceptor degeneration in CNG channel deficiency: evidence of cGMP cytotoxicity independently of enhanced CNG channel function.
abstract: Photoreceptor cyclic nucleotide-gated (CNG) channels regulate Ca(2+) 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 Ca(2+) influx.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, Center for Integrated Protein Science Munich and Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, 80539 Munich, Germany, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah 84132, and Department of Basic Sciences and Pennsylvania College of Optometry, Salus University, Elkins Park, Pennsylvania 19027.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xu
authors.forename: Lynsie
authors.initials: L
authors.lastname: Morris
authors.forename: Arjun
authors.initials: A
authors.lastname: Thapa
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ma
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: Igor V
authors.initials: IV
authors.lastname: Peshenko
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Dizhoor
authors.forename: Xi-Qin
authors.initials: XQ
authors.lastname: Ding
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency* / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000378:metabolism; D006162:Guanylate Cyclase / Q000172:deficiency / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010786:Photoreceptor Cells / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate; D012160:Retina / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C518237:Cnga3 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; D005136:Eye Proteins; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D017869:Cyclic GMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; C484780:Gucy2e protein, mouse; D006152:Cyclic GMP
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