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Retinal guanylyl cyclase isozyme 1 is the preferential in vivo target for constitutively active GCAP1 mutants causing congenital degeneration of photoreceptors
Journal article   Open access   Peer reviewed

Retinal guanylyl cyclase isozyme 1 is the preferential in vivo target for constitutively active GCAP1 mutants causing congenital degeneration of photoreceptors

Elena V Olshevskaya, Igor V Peshenko, Andrey B Savchenko and Alexander M Dizhoor
The Journal of neuroscience, v 32(21), pp 7208-7217
23 May 2012
DOI: https://doi.org/10.1523/JNEUROSCI.0976-12.2012
PMID: 22623665
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1523/jneurosci.0976-12.2012View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open
url
https://doi.org/10.1523/JNEUROSCI.0976-12.2012View
Published, Version of Record (VoR) Open

Abstract

Animals Calcium - pharmacology Cyclic GMP - metabolism Dose-Response Relationship, Drug Electroretinography - methods Female Guanylate Cyclase - genetics Guanylate Cyclase - metabolism Guanylate Cyclase - physiology Guanylate Cyclase-Activating Proteins - genetics Guanylate Cyclase-Activating Proteins - metabolism Guanylate Cyclase-Activating Proteins - physiology Isoenzymes - genetics Isoenzymes - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Retina - drug effects Retina - enzymology Retina - physiology Retinal Degeneration - metabolism Retinal Degeneration - pathology Retinal Degeneration - physiopathology Retinal Rod Photoreceptor Cells - enzymology Retinal Rod Photoreceptor Cells - pathology Retinal Rod Photoreceptor Cells - physiology
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 RetGC2 in vitro, we find that GCAP1 selectively regulates RetGC1 in 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 of RetGC1-/- genotype. The rod ERG recovery from a strong flash, only slightly affected in both RetGC1-/- and RetGC2-/- mice, becomes very slow in RetGC1-/- but not RetGC2-/- mice when GCAP2 is not available to provide Ca²⁺ feedback to the remaining RetGC isozyme. The intrinsic biochemical properties of RetGC and GCAP determined in vitro do 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.

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