cGMP/Protein Kinase G Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of Cyclic Nucleotide-gated Channel-deficient Mice

Ma, Hongwei; Butler, Michael R.; Thapa, Arjun; Belcher, J.H.; Yang, Fan; Baehr, Wolfgang; Biel, Martin; Michalakis, Stylianos; Ding, Xi

doi:10.1074/jbc.m115.641159

Cited by 40 publications

(78 citation statements)

References 56 publications

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“…When RetGC1 deceleration by Ca 2ϩ in the dark becomes less sensitive, a larger fraction of cGMP-gated channels in the plasma membrane maintains Ca 2ϩ influx in the dark, eventually provoking the onset of apoptosis (62,63). Stimulation of cGMP-dependent protein kinase activity can also lead to mouse photoreceptor death independently of the Ca 2ϩ pathway (64,65). In our present study, faster rod degeneration accompanied a larger shift in Ca 2ϩ sensitivity of the cGMP synthesis in the retina (Fig.…”

Section: What Processes Downstream Of the Mutated Cord6 Retgc1 Cause mentioning

confidence: 55%

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The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

Dizhoor

Peshenko

2016

Journal of Biological Chemistry

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Edited by Roger ColbranSubstitutions of Arg 838 in the dimerization domain of a human retinal membrane guanylyl cyclase 1 (RetGC1) linked to autosomal dominant cone-rod degeneration type 6 (CORD6) change RetGC1 regulation in vitro by Ca 2؉ . In addition, we find that R838S substitution makes RetGC1 less sensitive to inhibition by retinal degeneration-3 protein (RD3). We selectively expressed human R838S RetGC1 in mouse rods and documented the decline in rod vision and rod survival. To verify that changes in rods were specifically caused by the CORD6 mutation, we used for comparison cones, which in the same mice did not express R838S RetGC1 from the transgenic construct. The R838S RetGC1 expression in rod outer segments reduced inhibition of cGMP production in the transgenic mouse retinas at the free calcium concentrations typical for dark-adapted rods. The transgenic mice demonstrated early-onset and rapidly progressed with age decline in visual responses from the targeted rods, in contrast to the longer lasting preservation of function in the non-targeted cones. The decline in rod function in the retina resulted from a progressive degeneration of rods between 1 and 6 months of age, with the severity and pace of the degeneration consistent with the extent to which the Ca 2؉ sensitivity of the retinal cGMP production was affected. Our study presents a new experimental model for exploring cellular mechanisms of the CORD6-related photoreceptor death. This mouse model provides the first direct biochemical and physiological in vivo evidence for the Arg 838 substitutions in RetGC1 being the culprit behind the pathogenesis of the CORD6 congenital blindness.Retinal membrane guanylyl cyclase (RetGC) 2 is one of the key enzymes in vertebrate visual signaling. Rods and cones respond to light by closing cGMP-gated plasma membrane channels in the outer segment as cGMP becomes hydrolyzed by phosphodiesterase PDE6 and then re-open the channels, after PDE6 activity becomes quenched and cGMP becomes re-synthesized by RetGC (1-5). Two RetGC isozymes expressed in photoreceptors, , bind calcium-sensor proteins, GCAPs (7-12), which decelerate the cyclase activity at high intracellular calcium concentrations in the dark and accelerate it in the light, when the influx of calcium through the cGMP-gated channels is shut off (13)(14)(15)(16)(17)(18)(19). RetGC also binds retinal degeneration 3 (RD3) protein (20 -21), which prevents cyclase activation by GCAPs (22-23) and promotes accumulation of RetGC1 in the outer segments (21,24,25). RetGC1 (human gene GUCY2D) accounts for most of the cGMP synthesis in mammalian photoreceptors (26,27), therefore mutations in RetGC1 that disable the cyclase activity (28 -33) cause recessive blindness at birth, Leber congenital amaurosis type 1 (LCA1) (33), mostly a non-degenerative or partially degenerative (31, 32) loss-of-function hereditary retinal disease. Different from the LCA1 type of severe congenital blindness linked to the RetGC1 gene, cone-rod dystrophy type 6 (CORD6), is a progressive ear...

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Section: What Processes Downstream Of the Mutated Cord6 Retgc1 Cause mentioning

confidence: 55%

“…Unfolded Protein Response-Mutations in some proteins have shown propensity to provoke photoreceptor death by causing endoplasmic reticulum (ER) stress triggering apoptotic unfolded protein response (65,67). We find that the CORD6 mutant of RetGC1 is functional in vivo (Figs.…”

Section: What Processes Downstream Of the Mutated Cord6 Retgc1 Cause mentioning

confidence: 99%

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

Dizhoor

Peshenko

2016

Journal of Biological Chemistry

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“…Super‐Signal West Dura Extended Duration chemiluminescent substrate (Thermo Fisher Scientific) was used to detect binding of the primary antibodies to their cognate antigens. HyBlot CL autoradiography film (Denville Scientific, Inc., Metuchen, NJ, USA) was used to develop the target proteins, and Photoshop CS5 (Adobe Systems, Inc.)was used to analyze the signal density (26).…”

Section: Methodsmentioning

confidence: 99%

Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration

Yang

Belcher

et al. 2016

FASEB j.

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Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65 mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.

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“…Because of the lack of calcium entry through CNG channels and its continuous efflux through the NCKX exchangers, it can be expected that calcium levels in the CNG knockout photoreceptor would be abnormally low, and this would then lead to GCAPs-mediated stimulation of RetGCs. Prolonged elevation of cGMP, in turn, appears to activate protein kinase G (Ma et al, 2015; Paquet-Durand et al, 2009; Xu et al, 2013). In support of this mechanism, preventing protein kinase 1 expression had a rescuing effect on Cngb1 knockout rods (Wang et al, 2017).…”

Section: Role Of Calcium In Photoreceptor Degenerationmentioning

confidence: 99%

Regulation of calcium homeostasis in the outer segments of rod and cone photoreceptors

Vinberg

Chen

Kefalov

2018

Progress in Retinal and Eye Research

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Calcium plays important roles in the function and survival of rod and cone photoreceptor cells. Rapid regulation of calcium in the outer segments of photoreceptors is required for the modulation of phototransduction that drives the termination of the flash response as well as light adaptation in rods and cones. On a slower time scale, maintaining proper calcium homeostasis is critical for the health and survival of photoreceptors. Decades of work have established that the level of calcium in the outer segments of rods and cones is regulated by a dynamic equilibrium between influx via the transduction cGMP-gated channels and extrusion via rod- and cone-specific Na+/Ca2+, K+ exchangers (NCKXs). It had been widely accepted that the only mechanism for extrusion of calcium from rod outer segments is via the rod-specific NCKX1, while extrusion from cone outer segments is driven exclusively by the cone-specific NCKX2. However, recent evidence from mice lacking NCKX1 and NCKX2 have challenged that notion and have revealed a more complex picture, including a NCKX-independent mechanism in rods and two separate NCKX-dependent mechanisms in cones. This review will focus on recent findings on the molecular mechanisms of extrusion of calcium from the outer segments of rod and cone photoreceptors, and the functional and structural changes in photoreceptors when normal extrusion is disrupted.

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cGMP/Protein Kinase G Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of Cyclic Nucleotide-gated Channel-deficient Mice

Cited by 40 publications

References 56 publications

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration

Regulation of calcium homeostasis in the outer segments of rod and cone photoreceptors

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