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Temporal resolution of single photon responses in primate rod photoreceptors and limits imposed by cellular noise
摘要： Sensory receptor noise corrupts sensory signals, contributing to imperfect perception and dictating central processing strategies. For example, noise in rod phototransduction limits our ability to detect light and minimizing the impact of this noise requires precisely tuned nonlinear processing by the retina. But detection sensitivity is only one aspect of night vision: prompt and accurate behavior also requires that rods reliably encode the timing of photon arrivals. We show here that the temporal resolution of responses of primate rods is much finer than the duration of the light response and identify the key limiting sources of transduction noise. We also find that the thermal activation rate of rhodopsin is lower than previous estimates, implying that other noise sources are more important than previously appreciated. A model of rod single-photon responses reveals that the limiting noise relevant for behavior depends critically on how rod signals are pooled by downstream neurons.
关键词： thermal activation rate,primate rod photoreceptors,single photon responses,cellular noise,rhodopsin,temporal resolution
更新于2025-09-11 14:15:04
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Müller glia phagocytose dead photoreceptor cells in a mouse model of retinal degenerative disease
摘要： Retinitis pigmentosa is a devastating, blinding disorder that affects 1 in 4000 people worldwide. During the progression of the disorder, phagocytic clearance of dead photoreceptor cell bodies has a protective role by preventing additional retinal damage from accumulation of cellular debris. However, the cells responsible for the clearance remain unidentified. Taking advantage of a mouse model of retinitis pigmentosa (RhoP23H/P23H), we clarified the roles of M ¨uller glia in the phagocytosis of rod photoreceptor cells. During the early stage of retinal degeneration, M ¨uller glial cells participated in the phagocytosis of dying or dead rod photoreceptors throughout the outer nuclear layer. Nearly 50% of M ¨uller glia engaged in phagocytosis. Among the M ¨uller phagosomes, >90% matured into phagolysosomes. Those observations indicated that M ¨uller glial cells are the primary contributor to phagocytosis. In contrast, macrophages migrate to the inner part of the outer nuclear layer during photoreceptor degeneration, participating in the phagocytosis of a limited population of dying or dead photoreceptor cells. In healthy retinas of wild-type mice, M ¨uller glial cells phagocytosed cell bodies of dead rod photoreceptors albeit at a lower frequency. Taken together, the phagocytic function of M ¨uller glia is responsible for retinal homeostasis and reorganization under normal and pathologic conditions.
关键词： retinitis pigmentosa,phagocytosis,rod photoreceptors,rhodopsin
更新于2025-09-10 09:29:36
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Small-Angle Neutron Scattering Reveals Energy Landscape for Rhodopsin Photoactivation
摘要： Knowledge of the activation principles for G-protein-coupled receptors (GPCRs) is critical to development of new pharmaceuticals. Rhodopsin is the archetype for the largest GPCR family, yet the changes in protein dynamics that trigger signaling are not fully understood. Here we show that rhodopsin can be investigated by small-angle neutron scattering (SANS) in fully protiated detergent micelles under contrast matching to resolve light-induced changes in the protein structure. In SANS studies of membrane proteins, the zwitterionic detergent [(Cholamidopropyl)dimethylammonio]-propanesulfonate (CHAPS) is advantageous because of the low contrast difference between the hydrophobic core and hydrophilic head groups as compared to alkyl glycoside detergents. Combining SANS results with quasielastic neutron scattering (QENS) reveals how changes in volumetric protein shape are coupled (slaved) to the aqueous solvent. Upon light exposure rhodopsin is swollen by penetration of water into the protein core, allowing interactions with effector proteins in the visual signaling mechanism.
关键词： Detergent,Neutron Scattering,Hydration,GPCR,Protein Dynamics,Vision,Membrane Proteins,Energy landscape,Slaving,Rhodopsin
更新于2025-09-10 09:29:36
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Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease
摘要： G protein-coupled receptors (GPCRs) are crucial sensors of extracellular signals in eukaryotes, with multiple GPCR mutations linked to human diseases. With the growing number of sequenced human genomes, determining the pathogenicity of a mutation is challenging, but can be aided by a direct measurement of GPCR-mediated signaling. This is particularly difficult for the visual pigment rhodopsin, a GPCR activated by light, for which hundreds of mutations have been linked to inherited degenerative retinal diseases such as retinitis pigmentosa (RP). In this study, we successfully engineered, for the first time, activation by human rhodopsin of the yeast mating pathway, resulting in signaling via a fluorescent reporter. We combine this novel assay for rhodopsin light-dependent activation with studies of subcellular localization, and the upregulation of the unfolded protein response (UPR) in response to misfolded rhodopsin protein. We use these assays to characterize a panel of rhodopsin mutations with known molecular phenotypes, finding that rhodopsin maintains a similar molecular phenotype in yeast, with some interesting differences. Furthermore, we compare our assays in yeast with clinical phenotypes from patients with novel disease-linked mutations. We demonstrate that our engineered yeast strain can be useful in rhodopsin mutant classification, and in helping to determine the molecular mechanisms underlying their pathogenicity. This approach may also be applied to better understand the clinical relevance of other human GPCR mutations, furthering the use of yeast as a tool for investigating molecular mechanisms relevant to human disease.
关键词： disease model,G protein-coupled receptor,rhodopsin,Visual degenerative disease,retinitis pigmentosa
更新于2025-09-04 15:30:14