Novel Dominant Rhodopsin Mutation Triggers Two Mechanisms of Retinal Degeneration and Photoreceptor Desensitization

Iakhine, Roustem; Chorna-Ornan, Irit; Zars, Troy; Elia, Natalie; Cheng, Yan; Selinger, Zvi; Minke, Baruch; Hyde, David R.

doi:10.1523/jneurosci.5426-03.2004

Cited by 36 publications

(28 citation statements)

References 48 publications

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“…G␣ q Mutant Undergoes Slow Retinal Degeneration-Mutations in almost any gene that functions during phototransduction trigger rapid retinal degeneration, except the G␣ q 1 mutant, which undergoes slow retinal degeneration (34,43,44). In this study, we showed that the G␣ q 961 mutant undergoes slow lightdependent retinal degeneration, similar to that observed in the G␣ q 1 mutant (44).…”

supporting

confidence: 67%

Protein Gq Modulates Termination of Phototransduction and Prevents Retinal Degeneration

Wan

et al. 2012

Journal of Biological Chemistry

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Background: Appropriate termination of photoresponse is critical for photoreceptors to achieve high temporal resolution and to prevent excessive Ca 2ϩ -induced cell toxicity. Results: We isolated a novel G␣ q mutant allele and revealed that metarhodopsin/G q interaction affects Arr2-Rh1 binding. Conclusion: G q modulates the termination of phototransduction and prevents retinal degeneration. Significance: Our study revealed the novel role of G q in phototransduction deactivation and in retinal degeneration.Appropriate termination of the phototransduction cascade is critical for photoreceptors to achieve high temporal resolution and to prevent excessive Ca 2؉ -induced cell toxicity. Using a genetic screen to identify defective photoresponse mutants in Drosophila, we isolated and identified a novel G␣ q mutant allele, which has defects in both activation and deactivation. We revealed that G q modulates the termination of the light response and that metarhodopsin/G q interaction affects subsequent arrestin-rhodopsin (Arr2-Rh1) binding, which mediates the deactivation of metarhodopsin. We further showed that the G␣ q mutant undergoes light-dependent retinal degeneration, which is due to the slow accumulation of stable Arr2-Rh1 complexes. Our study revealed the roles of G q in mediating photoresponse termination and in preventing retinal degeneration. This pathway may represent a general rapid feedback regulation of G protein-coupled receptor signaling.Heterotrimeric G proteins play pivotal roles in mediating extracellular signals from hormones, neurotransmitters, peptides, as well as sensory stimuli to intracellular signaling pathways (1, 2). In Drosophila photoreceptors, G proteins are essential for the activation of the phototransduction cascade (3, 4). Photon absorption leads to the photoisomerization of chromophores, resulting in the formation of activated metarhodopsin. In turn, metarhodopsin activates heterotrimeric G proteins and PLC.2 The activation of PLC leads to transient receptor potential and transient receptor potential-like channels opening and extracellular Ca 2ϩ influx (5-8). It is also critical for each step of the phototransduction cascade to be terminated appropriately, which is essential for the high temporal resolution of fly vision (9, 10). The most important step in phototransduction termination is the deactivation of metarhodopsin. During this step, arrestin (Arr2) plays an important role by displacing the G q ␣ subunit and allowing it to bind with rhodopsin (Rh1) (11,12). Unlike other G proteincoupled receptors (GPCRs), the phosphorylation of fly rhodopsin is not required for its deactivation (13) but is essential for its endocytosis (11). In contrast, the dephosphorylation of rhodopsin by retinal degeneration C (RDGC) is essential for receptor deactivation (14). Ca 2ϩ also plays critical roles in regulating the termination of the photoresponse in Drosophila (8,15,16). Several proteins that mediate this Ca 2ϩ -regulated termination have been identified, such as eye-specific protein kinase C...

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confidence: 67%

Protein Gq Modulates Termination of Phototransduction and Prevents Retinal Degeneration

Wan

et al. 2012

Journal of Biological Chemistry

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“…Furthermore, a previous study has shown that the constitutively active rhodopsin mutant ninaE pp100 causes a stable association of the photopigment to Arr2 and thereby reduces the sensitivity to light by Ͼ10-fold (Iakhine et al, 2004). To examine the involvement of photopigment internalization in long-term adaptation, we examined whether photopigment phosphorylation plays a role in long-term adaptation.…”

Section: The Photopigment Cycle Is Not Involved In Long-term Adaptationmentioning

confidence: 99%

Translocation of G_qα Mediates Long-Term Adaptation inDrosophilaPhotoreceptors

Frechter

Elia²,

Tzarfaty³

et al. 2007

J. Neurosci.

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Light adaptation is a process that enables photoreceptor cells to operate over a wide range of light intensities without saturation. In invertebrate photoreceptors, fast adaptation is mediated by a Ca 2ϩ -dependent negative-feedback mechanism, which mainly affects the terminal steps of the cascade. Therefore, the response to each photon is smaller as light intensity increases, accommodating both high sensitivity and a vast dynamic range. Here, we describe a novel type of adaptation, which is mediated by one of the first steps in the phototransduction cascade affecting the sensitivity to absorbed photons. Long exposure to light resulted in dramatic reduction in the probability of each absorbed photon to elicit a response, whereas the size and shape of each single photon response did not change. To dissect the molecular mechanism underlying this form of adaptation we used a series of Drosophila mutants. Genetic dissection showed a pivotal role for light-induced translocation of G q ␣ between the signaling membrane and the cytosol. Biochemical studies revealed that the sensitivity to light depends on membrane G q ␣ concentration, which was modulated either by light or by mutations that impaired its targeting to the membrane. We conclude that long-term adaptation is mediated by the movement of G q ␣ from the signaling membrane to the cytosol, thereby reducing the probability of each photon to elicit a response. The slow time scale of this adaptation fits well with day/night light intensity changes, because there is no need to maintain single photon sensitivity during daytime.

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“…Constitutive or uncontrolled activity of rhodopsin can also lead to retinal degeneration, such as in the dominant allele, NinaE PP100 [222]. This retinal degeneration is partially suppressed by mutations in arr2 or Gα q , whereas complete suppression is achieved by disrupting both arr2 and the Gα q .…”

Section: Retinal Degenerationmentioning

confidence: 99%

Phototransduction and retinal degeneration in Drosophila

Wang

Montell

2007

Pflugers Arch - Eur J Physiol

261

303

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Drosophila visual transduction is the fastest known G-protein-coupled signaling cascade and has therefore served as a genetically tractable animal model for characterizing rapid responses to sensory stimulation. Mutations in over 30 genes have been identified, which affect activation, adaptation, or termination of the photoresponse. Based on analyses of these genes, a model for phototransduction has emerged, which involves phosphoinoside signaling and culminates with opening of the TRP and TRPL cation channels. Many of the proteins that function in phototransduction are coupled to the PDZ containing scaffold protein INAD and form a supramolecular signaling complex, the signalplex. Arrestin, TRPL, and Gα q undergo dynamic light-dependent trafficking, and these movements function in long-term adaptation. Other proteins play important roles either in the formation or maturation of rhodopsin, or in regeneration of phosphatidylinositol 4,5-bisphosphate (PIP 2 ), which is required for the photoresponse. Mutation of nearly any gene that functions in the photoresponse results in retinal degeneration. The underlying bases of photoreceptor cell death are diverse and involve mechanisms such as excessive endocytosis of rhodopsin due to stable rhodopsin/arrestin complexes and abnormally low or high levels of Ca 2+ . Drosophila visual transduction appears to have particular relevance to the cascade in the intrinsically photosensitive retinal ganglion cells in mammals, as the photoresponse in these latter cells appears to operate through a remarkably similar mechanism.

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Novel Dominant Rhodopsin Mutation Triggers Two Mechanisms of Retinal Degeneration and Photoreceptor Desensitization

Cited by 36 publications

References 48 publications

Protein Gq Modulates Termination of Phototransduction and Prevents Retinal Degeneration

Protein Gq Modulates Termination of Phototransduction and Prevents Retinal Degeneration

Translocation of G_qα Mediates Long-Term Adaptation inDrosophilaPhotoreceptors

Phototransduction and retinal degeneration in Drosophila

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Novel Dominant Rhodopsin Mutation Triggers Two Mechanisms of Retinal Degeneration and Photoreceptor Desensitization

Cited by 36 publications

References 48 publications

Protein Gq Modulates Termination of Phototransduction and Prevents Retinal Degeneration

Protein Gq Modulates Termination of Phototransduction and Prevents Retinal Degeneration

Translocation of Gqα Mediates Long-Term Adaptation inDrosophilaPhotoreceptors

Phototransduction and retinal degeneration in Drosophila

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Translocation of G_qα Mediates Long-Term Adaptation inDrosophilaPhotoreceptors