Effects of Low AIPL1 Expression on Phototransduction in Rods

Makino, Clint L.; Wen, Xiaohong; Michaud, Norman; Peshenko, Igor V.; Pawlyk, Basil; Brush, Richard S.; Soloviev, Maria; Liu, Xiaoqing; Woodruff, Michael L.; Calvert, Peter D.; Savchenko, A.; Anderson, Robert E.; Fain, Gordon; Li, Tiansen; Sandberg, Michael A.; Dizhoor, Alexander M.

doi:10.1167/iovs.05-1341

Cited by 17 publications

(17 citation statements)

References 48 publications

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“…The smaller peak amplitude was probably mostly attributable to a shorter than normal outer segment length, as we describe in detail below. The oscillations are probably the result of the shift in Ca 2ϩ sensitivity of the cyclase and hence the increase in cyclase activity; they were seen previously in recordings from L53 Y99C rods (i.e., Y99C ϩ/Ϫ ;R ϩ/ϩ ) (Makino et al, 2006), although they are larger and more consistently observed in our recent recordings from the Y99C ϩ/Ϫ ;R ϩ/Ϫ rods. Responses from G90D rods (Fig.…”

Section: ؉supporting

confidence: 72%

“…Although the outer segments in the Y99C/G90D rods were Ͻ80% their normal length, even in 6-month-old animals we did not observe distortion in disk stacking (Fig. 5e) as in parental Y99C L53 mice (Makino et al, 2006). The restoration of the photoreceptor layer in Y99C/G90D mice occurred along the whole extent of the retina rather than in distinct patches (Fig.…”

Section: Camentioning

confidence: 59%

“…In the animals we examined, degeneration is correlated with the increased circulating current density that produces an increase in intracellular Ca 2ϩ , Makino et al, 2006 (Fig. 4b, Table 1).…”

Section: Discussionmentioning

confidence: 94%

“…One such mutation, Tyr99Cys (Y99C) in GCAP-1, shifts the Ca 2ϩ sensitivity of the cyclase (Dizhoor et al, 1998;Sokal et al, 1998;Wilkie et al, 2000Wilkie et al, , 2001 and increases both cGMP and free Ca 2ϩ in resting photoreceptors of transgenic mice that degenerate after the increase in Ca 2ϩ concentration Makino et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Constitutive Excitation by Gly90Asp Rhodopsin Rescues Rods from Degeneration Caused by Elevated Production of cGMP in the Dark

et al. 2007

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Previous experiments indicate that congenital human retinal degeneration caused by genetic mutations that change the Ca 2ϩ sensitivity of retinal guanylyl cyclase (retGC) can result from an increase in concentration of free intracellular cGMP and Ca 2ϩ in the photoreceptors. To rescue degeneration in transgenic mouse models having either the Y99C or E155G mutations of the retGC modulator guanylyl cyclase-activating protein 1 (GCAP-1), which produce elevated cGMP synthesis in the dark, we used the G90D rhodopsin mutation, which produces constitutive stimulation of cGMP hydrolysis. The effects of the G90D transgene were evaluated by measuring retGC activity biochemically, by recording single rod and electroretinogram (ERG) responses, by intracellular free Ca 2ϩ measurement, and by retinal morphological analysis. Although the G90D rhodopsin did not alter the abnormal Ca 2ϩ sensitivity of retGC in the double-mutant animals, the intracellular free cGMP and Ca 2ϩ concentrations returned close to normal levels, consistent with constitutive activation of the phosphodiesterase PDE6 cascade in darkness. G90D decreased the light sensitivity of rods but spared them from severe retinal degeneration in Y99C and E155G GCAP-1 mice. More than half of the photoreceptors remained alive, appeared morphologically normal, and produced electrical responses, at the time when their siblings lacking the G90D rhodopsin transgene lost the entire retinal outer nuclear layer and no longer responded to illumination. These experiments indicate that mutations that lead to increases in cGMP and Ca 2ϩ can trigger photoreceptor degeneration but that constitutive activation of the transduction cascade in these animals can greatly enhance cell survival.

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Section: ؉supporting

confidence: 72%

Section: Camentioning

confidence: 59%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Constitutive Excitation by Gly90Asp Rhodopsin Rescues Rods from Degeneration Caused by Elevated Production of cGMP in the Dark

et al. 2007

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“…Of the fifteen genes known, AIPL1 is known to cause the most severe form of LCA. It encodes for essential protein required for the proper functioning of the rod photodiestrase enzyme thereby aiding proper vision [2]. The gene locus of AIPL1 is on chromosome 17p13 [3].…”

Section: Introductionmentioning

confidence: 99%

Structural studies on AIPL1 and its functional interactions with NUB1 to identify key interacting residues in LCA4

Muthukumaran¹,

Vetrivel²,

Valliappan

2012

j ocul biol dis inform

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Leber congenital amaurosis (LCA) is an autosomal recessive disorder that causes visual impairment in children due to fifteen different gene mutations. Of these, mutations in Aryl-Hydrocarbon Receptor Interacting Protein-like 1 (AIPL1) cause the most severe form of LCA (LCA4) leading to the degeneration of photoreceptor cells. NEDD8 Ultimate Buster 1 (NUB1), a protein that regulates cell cycle progression, interacts with AIPL1 to prevent the over expression of NUB1. In the case of over expression, cell cycle progression is disrupted and may lead to LCA. The studies on interactions between these two proteins will aid in identifying potential modulators for this condition. Since no three-dimensional structure is currently available for these two proteins, in this study we predicted the structures of these two proteins by molecular modelling methods. Moreover, we also modelled the three proven significant mutant forms of AIPL1 spanning the tetratricopeptide domain. Finally, both the modelled wild and mutant structures of AIPL1 (A197P, C239R and G262S) were computationally docked to NUB1, so as to map the potential molecular interactions. This is the first study on modelling the structure-function relationship of AIPL1-NUB1 interactions which shall aid in discovery of novel therapeutic agents.

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Overexpression of Rhodopsin Alters the Structure and Photoresponse of Rod Photoreceptors

Wen

Shen

Brush

et al. 2009

Biophysical Journal

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Rhodopsins are densely packed in rod outer-segment membranes to maximize photon absorption, but this arrangement interferes with transducin activation by restricting the mobility of both proteins. We attempted to explore this phenomenon in transgenic mice that overexpressed rhodopsin in their rods. Photon capture was improved, and, for a given number of photoisomerizations, bright-flash responses rose more gradually with a reduction in amplification--but not because rhodopsins were more tightly packed in the membrane. Instead, rods increased their outer-segment diameters, accommodating the extra rhodopsins without changing the rhodopsin packing density. Because the expression of other phototransduction proteins did not increase, transducin and its effector phosphodiesterase were distributed over a larger surface area. That feature, as well as an increase in cytosolic volume, was responsible for delaying the onset of the photoresponse and for attenuating its amplification.

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Effects of Low AIPL1 Expression on Phototransduction in Rods

Cited by 17 publications

References 48 publications

Constitutive Excitation by Gly90Asp Rhodopsin Rescues Rods from Degeneration Caused by Elevated Production of cGMP in the Dark

Constitutive Excitation by Gly90Asp Rhodopsin Rescues Rods from Degeneration Caused by Elevated Production of cGMP in the Dark

Structural studies on AIPL1 and its functional interactions with NUB1 to identify key interacting residues in LCA4

Overexpression of Rhodopsin Alters the Structure and Photoresponse of Rod Photoreceptors

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