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Retinal Guanylyl Cyclase Isozyme 1 Is the PreferentialIn VivoTarget for Constitutively Active GCAP1 Mutants Causing Congenital Degeneration of Photoreceptors
- Source :
- The Journal of Neuroscience. 32:7208-7217
- Publication Year :
- 2012
- Publisher :
- Society for Neuroscience, 2012.
-
Abstract
- Two calcium-sensitive guanylyl cyclase activating proteins (GCAP1 and GCAP2) activate cGMP synthesis in photoreceptor by retinal membrane guanylyl cyclase isozymes (RetGC1 and RetGC2) to expedite recovery, but calcium-insensitive constitutively active GCAP1 mutants cause photoreceptor degeneration in human patients and transgenic mice. Although GCAP1 and GCAP2 can both activate RetGC1 and RetGC2in vitro, we find that GCAP1 selectively regulates RetGC1in vivo. Furthermore, elimination of RetGC1 but not RetGC2 isozyme reverses abnormal calcium sensitivity of cGMP synthesis and rescues mouse rods in transgenic mice expressing GCAP1 mutants causing photoreceptor disease. Rods expressing mutant GCAP1 not only survive in the absence of RetGC1 but also remain functional, albeit with reduced electroretinography (ERG) amplitudes typical ofRetGC1−/−genotype. The rod ERG recovery from a strong flash, only slightly affected in bothRetGC1−/−andRetGC2−/−mice, becomes very slow inRetGC1−/−but notRetGC2−/−mice when GCAP2 is not available to provide Ca2+feedback to the remaining RetGC isozyme. The intrinsic biochemical properties of RetGC and GCAP determinedin vitrodo not explain the observed phenomena. Instead, our results argue that there must be a cellular mechanism that limits GCAP1 access to RetGC2 and makes RetGC1 isozyme a preferential target for the disease-causing GCAP1 mutants. A more general conclusion from our findings is that nondiscriminatory interactions between homologous effector enzymes and their regulatory proteins permitted by their intrinsic biochemical properties can be effectively restricted in a living photoreceptor.
- Subjects :
- Male
Genetically modified mouse
Retinal degeneration
genetic structures
Mutant
Mice, Transgenic
Biology
Isozyme
Retina
Article
Mice
chemistry.chemical_compound
Retinal Rod Photoreceptor Cells
Electroretinography
medicine
Animals
Cyclic GMP
Mice, Knockout
Dose-Response Relationship, Drug
medicine.diagnostic_test
General Neuroscience
Retinal Degeneration
Retinal
medicine.disease
Guanylate Cyclase-Activating Proteins
Cell biology
Isoenzymes
Mice, Inbred C57BL
medicine.anatomical_structure
Biochemistry
chemistry
Guanylate Cyclase
Calcium
Female
sense organs
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 32
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....fd5f231a9c43a4bed3165e9f3464eadf