Support for the equivalent light hypothesis for RP

Lisman, John; Fain, Gordon

doi:10.1038/nm1295-1254

Cited by 64 publications

(40 citation statements)

References 16 publications

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“…However, other transgenic mice with prolonged photoresponses, such as those lacking arrestin, also show light-dependent morphological abnormalities (23). Thus, a plausible hypothesis is that prolonged activation of the phototransduction cascade induces outer segment shortening (24) and eventual photoreceptor death (25,26). If so, such light effects should be suppressed by deletion of protein(s) responsible for activation of the cascade.…”

Section: Discussionmentioning

confidence: 99%

Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase

Chen

Burns

Spencer

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

302

307

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Phosphorylation is thought to be an essential first step in the prompt deactivation of photoexcited rhodopsin. In vitro, the phosphorylation can be catalyzed either by rhodopsin kinase (RK) or by protein kinase C (PKC). To investigate the specific role of RK, we inactivated both alleles of the RK gene in mice. This eliminated the light-dependent phosphorylation of rhodopsin and caused the single-photon response to become larger and longer lasting than normal. These results demonstrate that RK is required for normal rhodopsin deactivation. When the photon responses of RK؊͞؊ rods did finally turn off, they did so abruptly and stochastically, revealing a first-order backup mechanism for rhodopsin deactivation. The rod outer segments of RK؊͞؊ mice raised in 12-hr cyclic illumination were 50% shorter than those of normal (RK؉͞؉) rods or rods from RK؊͞؊ mice raised in constant darkness. One day of constant light caused the rods in the RK؊͞؊ mouse retina to undergo apoptotic degeneration. Mice lacking RK provide a valuable model for the study of Oguchi disease, a human RK deficiency that causes congenital stationary night blindness.

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Section: Discussionmentioning

confidence: 99%

Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase

Chen

Burns

Spencer

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

302

307

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“…The equivalent constant light hypothesis postulates that rhodopsin mutants constitutively activate the phototransduction cascade (15,16), creating a situation that is analogous to constant exposure to environmental light, a known cause of photoreceptor degeneration. So far, studies in vivo have not supported this hypothesis (11,13,(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

Transgenic mice carrying the dominant rhodopsin mutation P347S: Evidence for defective vectorial transport of rhodopsin to the outer segments

Snyder

Olsson

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

217

212

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To explore the pathogenic mechanism of dominant mutations affecting the carboxyl terminus of rhodopsin that cause retinitis pigmentosa, we generated five lines of transgenic mice carrying the proline-347 to serine (P347S) mutation. The severity of photoreceptor degeneration correlated with the levels of transgene expression in these lines. Visual function as measured by the electroretinogram was approximately normal at an early age when there was little histologic evidence of photoreceptor degeneration, but it deteriorated as photoreceptors degenerated. Immunocytochemical staining showed the mutant rhodopsin predominantly in the outer segments prior to histologically evident degeneration, a finding supported by quantitation of signal intensities in different regions of the photoreceptor cells by confocal microscopy. A distinct histopathologic abnormality was the accumulation of submicrometer-sized vesicles extracellularly near the junction between inner and outer segments. The extracellular vesicles were bound by a single membrane that apparently contained rhodopsin as revealed by ultrastructural immunocytochemical staining with anti-rhodopsin antibodies. The outer segments, although shortened, contained well-packed discs. Proliferation of the endoplasmic reticulum as reported in Drosophila expressing dominant rhodopsin mutations was not observed. The accumulation of rhodopsinladen vesicles likely represents aberrant transport of rhodopsin from the inner segments to the nascent disc membranes of the outer segments. It is possible that photoreceptor degeneration occurs because of a failure to renew outer segments at a normal rate, thereby leading to a progressive shortening of outer segments, or because of the loss of cellular contents to the extracellular space, or because of both.

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“…The large number of mutations and their different location along the polypeptide chain indicate a highly sophisticated arrangement of physicochemical interactions in the three-dimensional structure of the native molecule. Although protein misfolding or altered trafficking is considered to be the major biochemical features of many RP mutations in Rh (16 -19), some mutations do not induce major structural defects (20,21) but cause changes in G-protein binding and activation (22,23) or the formation of altered photointermediates (24,25), among other phenotypes (17,(25)(26)(27)(28). Sector RP is an atypical form of RP, ranging from stationary to slowly progressive evolution of the retinal degenerative pattern, characterized by regional areas of bone spicule pigmentation, subnormal electroretinogram, and visual-field defects, usually in the inferior quadrant of the retina (29,30).…”

Section: Rpmentioning

confidence: 99%

Differential Light-induced Responses in Sectorial Inherited Retinal Degeneration

Ramon

Cordomí

Aguilà

et al. 2014

Journal of Biological Chemistry

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Background:Two new rhodopsin mutations associated with the rare form sector retinitis pigmentosa (RP) have been found. Results: Characterization of both rhodopsin mutant proteins shows different progression correlating with a different behavior of rhodopsin upon light exposure. Conclusion: Light plays an important role in triggering sector RP. Significance: Other mechanisms, in addition to protein misfolding, underlie GPCR dysfunction in pathological processes.

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Support for the equivalent light hypothesis for RP

Cited by 64 publications

References 16 publications

Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase

Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase

Transgenic mice carrying the dominant rhodopsin mutation P347S: Evidence for defective vectorial transport of rhodopsin to the outer segments

Differential Light-induced Responses in Sectorial Inherited Retinal Degeneration

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