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Elena V. Olshevskaya, Andrey B. Savchenko, Igor V. Peshenko, Alexander M. Dizhoor; The Absence Of Retinal Guanylyl Cyclase Isozyme 1 (RetGC1) Protects Mouse Rods From Rapid Degeneration Caused By Ca2+-insensitive Mutants Of GCAP1. Invest. Ophthalmol. Vis. Sci. 2011;52(14):31.
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Mutations, Y99C or E155G, in guanylyl cyclase activating protein 1 (GCAP1) linked to human retinal dystrophy shift Ca2+-sensitivity of the retinal guanylyl cyclase (RetGC) in transgenic mouse models beyond the normal intracellular Ca2+ range in rods. This causes abnormal elevation of cGMP and Ca2+ in dark-adapted photoreceptors and triggers severe retinal degeneration. The purpose of this study was to determine, which RetGC isozyme, RetGC1 or RetGC2, is the main target for the mutant GCAP1 in triggering rod death.
We removed RetGC1 by transferring transgenic expression of the Y99C or E155G GCAP1 to the mouse RetGC1-/- background and characterized the morphological, biochemical and electrophysiological properties of their retinas.
Retinal morphology, the RetGC activity, and electroretinography (ERG) responses in mice expressing mutant GCAP1 in the presence and in the absence of RetGC1 were strikingly different from each other. The rate of cGMP synthesis was reduced due to the lack of RetGC1, but Ca2+ regulation of the remaining isozyme, RetGC2, was not shifted toward the higher Ca2+ range typical for the Y99C or E155G rods expressing both RetGC isozymes. Elimination of the RetGC1 strongly suppressed the rate of retinal degeneration in both Y99C+:RetGC1-/- and E155G+:RetGC1-/- mice and dramatically improved retinal morphology and ERG responses at the ages when the Y99C+:RetGC1+/+ and E155G+:RetGC1+/+ mice develop obliteration of photoreceptors and complete loss of ERG a-wave.
Despite the ability of GCAP1 to activate both RetGC1 and RetGC2 in vitro, RetGC1 isozyme is the main target for the Y99C or E155G GCAP1 that disrupt Ca2+ feedback for cGMP synthesis in the affected photoreceptors in vivo. The Y99C GCAP1 does not regulate RetGC2 in living rods.
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