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Journal article
The Y99C mutation in guanylyl cyclase-activating protein 1 increases intracellular Ca2+ and causes photoreceptor degeneration in transgenic mice
The Journal of neuroscience, v 24(27), pp 6078-6085
07 Jul 2004
PMID: 15240799
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Guanylyl cyclase-activating proteins (GCAPs) are Ca2+-binding proteins that activate guanylyl cyclase when free Ca2+ concentrations in retinal rods and cones fall after illumination and inhibit the cyclase when free Ca2+ reaches its resting level in the dark. Several forms of retinal dystrophy are caused by mutations in GUCA1A, the gene coding for GCAP1. To investigate the cellular mechanisms affected by the diseased state, we created transgenic mice that express GCAP1 with a Tyr99Cys substitution (Y99C GCAP1) found in human patients with a late-onset retinal dystrophy (Payne et al., 1998). Y99C GCAP1 shifted the Ca2+ sensitivity of the guanylyl cyclase in photoreceptors, keeping it partially active at 250 nM free Ca2+, the normal resting Ca2+ concentration in darkness. The enhanced activity of the cyclase in the dark increased cyclic nucleotide-gated channel activity and elevated the rod outer segment Ca2+ concentration in darkness, measured by using fluo-5F and laser spot microscopy. In different lines of transgenic mice the magnitude of this effect rose with the Y99C GCAP1 expression. Surprisingly, there was little change in the rod photoresponse, indicating that dynamic Ca2+-dependent regulation of cGMP synthesis was preserved. However, the photoreceptors in these mice degenerated, and the rate of the cell loss increased with the level of the transgene expression, unlike in transgenic mice that overexpressed normal GCAP1. These results provide the first direct evidence that a mutation linked to congenital blindness increases Ca2+ in the outer segment, which may trigger the apoptotic process.
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Details
- Title
- The Y99C mutation in guanylyl cyclase-activating protein 1 increases intracellular Ca2+ and causes photoreceptor degeneration in transgenic mice
- Creators
- Elena V Olshevskaya - Salus UniversityPeter D Calvert - Massachusetts Eye and Ear InfirmaryMichael L Woodruff - Department of Physiological SciencesIgor V Peshenko - Salus UniversityAndrey B Savchenko - Salus UniversityClint L Makino - Massachusetts Eye and Ear InfirmaryYe-Shih Ho - Wayne State UniversityGordon L Fain - University of California, Los AngelesAlexander M Dizhoor - Salus University
- Publication Details
- The Journal of neuroscience, v 24(27), pp 6078-6085
- Publisher
- Society for Neuroscience
- Number of pages
- 8
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Web of Science ID
- WOS:000222491000005
- Scopus ID
- 2-s2.0-3042789501
- Other Identifier
- 991022035115604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences