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Journal article
Retinal guanylyl cyclase activation by calcium sensor proteins mediates photoreceptor degeneration in an rd3 mouse model of congenital human blindness
The Journal of biological chemistry, v 294(37), pp 13729-13739
13 Sep 2019
PMID: 31346032
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Deficiency of RD3 (retinal degeneration 3) protein causes recessive blindness and photoreceptor degeneration in humans and in the rd3 mouse strain, but the disease mechanism is unclear. Here, we present evidence that RD3 protects photoreceptors from degeneration by competing with guanylyl cyclase-activating proteins (GCAPs), which are calcium sensor proteins for retinal membrane guanylyl cyclase (RetGC). RetGC activity in rd3/rd3 retinas was drastically reduced but stimulated by the endogenous GCAPs at low Ca2+ concentrations. RetGC activity completely failed to accelerate in rd3/rd3GCAPs(-/-) hybrid photoreceptors, whose photoresponses remained drastically suppressed compared with the WT. However, similar to 70% of the hybrid rd3/rd3GCAPs(-/-) photoreceptors survived past 6 months, in stark contrast to <5% in the nonhybrid rd3/rd3 retinas. GFP-tagged human RD3 inhibited GCAP-dependent activation of RetGC in vitro similarly to the untagged RD3. When transgenically expressed in rd3/rd3 mouse retinas under control of the rhodopsin promoter, the RD3GFP construct increased RetGC levels to near normal levels, restored dark-adapted photoresponses, and rescued rods from degeneration. The fluorescence of RD3GFP in rd3/rd3RD3GFP(+) retinas was mostly restricted to the rod photoreceptor inner segments, whereas GCAP1 immunofluorescence was concentrated predominantly in the outer segment. However, RD3GFP became distributed to the outer segments when bred into a GCAPs(-/-) genetic background. These results support the hypothesis that an essential biological function of RD3 is competition with GCAPs that inhibits premature cyclase activation in the inner segment. Our findings also indicate that the fast rate of degeneration in RD3-deficient photoreceptors results from the lack of this inhibition.
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Details
- Title
- Retinal guanylyl cyclase activation by calcium sensor proteins mediates photoreceptor degeneration in an rd3 mouse model of congenital human blindness
- Creators
- Alexander M. Dizhoor - Salus UniversityElena V. Olshevskaya - Salus UniversityIgor V. Peshenko - Salus University
- Publication Details
- The Journal of biological chemistry, v 294(37), pp 13729-13739
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Number of pages
- 11
- Grant note
- Pennsylvania Department of Health R01EY011522 / NATIONAL EYE INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Eye Institute (NEI) EY011522 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Web of Science ID
- WOS:000486418600018
- Scopus ID
- 2-s2.0-85072234083
- Other Identifier
- 991022035260604721
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- Web of Science research areas
- Biochemistry & Molecular Biology