RDS in Cones Does Not Interact with the Beta Subunit of the Cyclic Nucleotide Gated Channel

Invest. Ophthalmol. Vis. Sci.

DeRamus

et al. 2015

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PURPOSE. The beta subunit of the rod cyclic nucleotide gated channel B1 (CNGB1) contains a proline/glutamic acid-rich N-terminal domain (GARP), which is also present in rods as a nonmembrane-bound protein (GARP1/2). GARP2 and CNGB1 bind to retinal degeneration slow (RDS), which is present in the rims of rod and cone outer segment (OS) layers. Here we focus on the importance of RDS/GARP complexes in OS morphogenesis and stability. METHODS.Retinal structure, function, and biochemistry were assessed in GARP2-Tg transgenic mice crossed onto rds, and rds À/À genetic backgrounds.RESULTS. GARP2 expression decreased in animals with reduced RDS levels. Overexpression of GARP2 led to abnormalities in disc stacking in GARP2-Tg/rds þ/þ and the accumulation of abnormal vesicular structures in GARP2-Tg/rds þ/À OS, as well as alterations in RDS-ROM-1 complex formation. These abnormalities were associated with diminished scotopic a-and bwave amplitudes in GARP2-Tg mice on both the rds þ/þ and rds þ/À backgrounds. In addition, severe defects in cone function were observed in GARP2-Tg mice on all RDS backgrounds. CONCLUSIONS.Our results indicate that overexpression of GARP2 significantly exacerbates the defects in rod function associated with RDS haploinsufficiency and leads to further abnormalities in OS ultrastructure. These data also suggest that GARP2 expression in cones can be detrimental to cones. RDS/GARP interactions remain under investigation but are critical for both OS structure and function.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Varying the GARP2-to-RDS Ratio Leads to Defects in Rim Formation and Rod and Cone Function

Chakraborty

Invest. Ophthalmol. Vis. Sci.

DeRamus

et al. 2015

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“…The cone CNGB subunit does not have a GARP region or free GARP isoforms and PRPH2/RDS does not interact cone CNGB channel (Conley et al, 2010a). The precise role of PRPH2/RDS interactions with other proteins, such as GARP, to OS organization is not clearly established, however the model that these interactions play an important role in OS organization is well-supported.…”

Section: Role Of Prph2/rds In the Photoreceptormentioning

confidence: 99%

PRPH2/RDS and ROM-1: Historical context, current views and future considerations

Stuck

Progress in Retinal and Eye Research

Naash

2016

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106

Peripherin2 (PRPH2), also known as RDS (retinal degeneration slow) is a photoreceptor specific glycoprotein which is essential for normal photoreceptor health and vision. PRPH2/RDS is necessary for the proper formation of both rod and cone photoreceptor outer segments, the organelle specialized for visual transduction. When PRPH2/RDS is defective or absent, outer segments become disorganized or fail to form entirely and the photoreceptors subsequently degenerate. Multiple PRPH2/RDS disease-causing mutations have been found in humans, and they are associated with various blinding diseases of the retina such as macular degeneration and retinitis pigmentosa, the vast majority of which are inherited dominantly, though recessive LCA and digenic RP have also been associated with RDS mutations. Since its initial discovery, the scientific community has dedicated a considerable amount of effort to understanding the molecular function and disease mechanisms of PRPH2/RDS. This work has led to an understanding of how the PRPH2/RDS molecule assembles into complexes and functions as a necessary part of the machinery that forms new outer segment discs, as well as leading to fundamental discoveries about the mechanisms that underlie OS biogenesis. Here we discuss PRPH2/RDS-associated research and how experimental results have driven the understanding of the PRPH2/RDS protein and its role in human disease.

“…In addition, in rods, RDS in the OS binds to the GARP portion of the b-subunit of the CNG channel, possibly tethering disc rims to the plasma membrane (28). In cones, this stabilizing interaction is absent; the cone CNG channel does not have a GARP portion, and RDS does not interact with the channel (29). Cone rims may be therefore more susceptible to disruption than rod rims, and require additional structural support from disulfide-bonded RDS complexes to keep them intact.…”

Section: C150s-rdsmentioning

confidence: 99%

Differences in RDS trafficking, assembly and function in cones versus rods: insights from studies of C150S-RDS

Chakraborty

Human Molecular Genetics

Stuck

et al. 2010

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Cysteine 150 of retinal degeneration slow protein (RDS) mediates the intermolecular disulfide bonding necessary for large RDS complex assembly and morphogenesis of the rim region of photoreceptor outer segments. Previously, we showed that cones have a different requirement for RDS than rods, but the nature of that difference was unclear. Here, we express oligomerization-incompetent RDS (C150S-RDS) in the conedominant nrl 2/2 mouse. Expression of C150S-RDS leads to dominant functional abnormalities, ultrastructural changes, biochemical anomalies and protein mislocalization in cones. These data suggest that RDS complexes in cones are more susceptible to disruption than those in rods, possibly due to structural or microenvironmental differences in the two cell types. Furthermore, our results suggest that RDS intermolecular disulfide bonding may be part of RDS inner-segment assembly in cones but not in rods. These data highlight significant differences in assembly, trafficking and function of RDS in rods versus cones.