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Constitutive excitation by Gly90Asp rhodopsin rescues rods from degeneration caused by elevated production of cGMP in the dark.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2007 Aug 15; Vol. 27 (33), pp. 8805-15. - Publication Year :
- 2007
-
Abstract
- Previous experiments indicate that congenital human retinal degeneration caused by genetic mutations that change the Ca(2+) sensitivity of retinal guanylyl cyclase (retGC) can result from an increase in concentration of free intracellular cGMP and Ca(2+) in the photoreceptors. To rescue degeneration in transgenic mouse models having either the Y99C or E155G mutations of the retGC modulator guanylyl cyclase-activating protein 1 (GCAP-1), which produce elevated cGMP synthesis in the dark, we used the G90D rhodopsin mutation, which produces constitutive stimulation of cGMP hydrolysis. The effects of the G90D transgene were evaluated by measuring retGC activity biochemically, by recording single rod and electroretinogram (ERG) responses, by intracellular free Ca(2+) measurement, and by retinal morphological analysis. Although the G90D rhodopsin did not alter the abnormal Ca(2+) sensitivity of retGC in the double-mutant animals, the intracellular free cGMP and Ca(2+) concentrations returned close to normal levels, consistent with constitutive activation of the phosphodiesterase PDE6 cascade in darkness. G90D decreased the light sensitivity of rods but spared them from severe retinal degeneration in Y99C and E155G GCAP-1 mice. More than half of the photoreceptors remained alive, appeared morphologically normal, and produced electrical responses, at the time when their siblings lacking the G90D rhodopsin transgene lost the entire retinal outer nuclear layer and no longer responded to illumination. These experiments indicate that mutations that lead to increases in cGMP and Ca(2+) can trigger photoreceptor degeneration but that constitutive activation of the transduction cascade in these animals can greatly enhance cell survival.
- Subjects :
- Adaptation, Ocular genetics
Animals
Calcium metabolism
Cyclic GMP genetics
Cysteine genetics
Dark Adaptation genetics
Dark Adaptation physiology
Disease Models, Animal
Electroretinography methods
Gene Expression Regulation radiation effects
Guanylate Cyclase-Activating Proteins genetics
Mice
Mice, Transgenic
Microscopy, Electron, Transmission methods
Physical Stimulation methods
Retina pathology
Retina physiopathology
Retinal Degeneration genetics
Retinal Degeneration pathology
Retinal Degeneration physiopathology
Retinal Rod Photoreceptor Cells ultrastructure
Rhodopsin genetics
Tyrosine genetics
Aspartic Acid genetics
Cyclic GMP metabolism
Glycine genetics
Guanylate Cyclase-Activating Proteins metabolism
Retinal Degeneration metabolism
Retinal Rod Photoreceptor Cells physiopathology
Rhodopsin physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 27
- Issue :
- 33
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 17699662
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.2751-07.2007