Rod and Cone Visual Pigments and Phototransduction through Pharmacological, Genetic, and Physiological Approaches

Kefalov, Vladimir J.

doi:10.1074/jbc.r111.303008

Cited by 82 publications

(63 citation statements)

References 90 publications

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“…Rods are highly sensitive and able to respond to single photons, thus setting absolute visual threshold. Cones are less sensitive but can respond to a broad range of light intensities of specific wavelengths and thus are essential for daytime and color vision (Kefalov, 2012; Korenbrot, 2012). The functional differences between rod and cone photoresponses are carried downstream through their selective connectivity with distinct classes of bipolar cells (BCs) forming established circuits with known properties that are conserved across vertebrate species (Ghosh et al, 2004; Lamb, 2013; Pahlberg and Sampath, 2011).…”

Section: Introductionmentioning

confidence: 99%

Mechanism for Selective Synaptic Wiring of Rod Photoreceptors into the Retinal Circuitry and Its Role in Vision

Cao

Sarria

Fehlhaber

et al. 2015

Neuron

107

169

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SUMMARY In the retina, rod and cone photoreceptors form distinct connections with different classes of downstream bipolar cells. However, the molecular mechanisms responsible for their selective connectivity are unknown. Here we identify a cell-adhesion protein, ELFN1, to be essential for the formation of synapses between rods and rod ON-bipolar cells in the primary rod pathway. ELFN1 is expressed selectively in rods where it is targeted to the axonal terminals by the synaptic release machinery. At the synapse, ELFN1 binds in trans to mGluR6, the postsynaptic receptor on rod ON-bipolar cells. Elimination of ELFN1 in mice prevents the formation of synaptic contacts involving rods, but not cones, allowing a dissection of the contributions of primary and secondary rod pathways to retinal circuit function and vision. We conclude that ELFN1 is necessary for the selective wiring of rods into the primary rod pathway and is required for high sensitivity of vision.

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Section: Introductionmentioning

confidence: 99%

Mechanism for Selective Synaptic Wiring of Rod Photoreceptors into the Retinal Circuitry and Its Role in Vision

Cao

Sarria

Fehlhaber

et al. 2015

Neuron

107

169

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“…Cone opsins operate in high-light conditions and thus have to rapidly respond to new photons without losing sensitivity. Therefore, their faster recovery to the inactive state (25,40,41), due to a rapid collapse to an inactive (Ops) conformation, would discourage ATR rebinding (and thus persistence of signaling) and be essential for maintaining the ability to discriminate differences in light intensity during daylight conditions (25). In contrast, rhodopsin, the dim-light photoreceptor, needs to convert a single photon into a maximal neuronal signal.…”

Section: After Rhodopsin Photoactivation An Equilibrium Of Atr Releamentioning

confidence: 99%

Decay of an active GPCR: Conformational dynamics govern agonist rebinding and persistence of an active, yet empty, receptor state

Schafer

Fay

Janz

et al. 2016

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

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Here, we describe two insights into the role of receptor conformational dynamics during agonist release (all-trans retinal, ATR) from the visual G protein-coupled receptor (GPCR) rhodopsin. First, we show that, after light activation, ATR can continually release and rebind to any receptor remaining in an active-like conformation. As with other GPCRs, we observe that this equilibrium can be shifted by either promoting the active-like population or increasing the agonist concentration. Second, we find that during decay of the signaling state an active-like, yet empty, receptor conformation can transiently persist after retinal release, before the receptor ultimately collapses into an inactive conformation. The latter conclusion is based on timeresolved, site-directed fluorescence labeling experiments that show a small, but reproducible, lag between the retinal leaving the protein and return of transmembrane helix 6 (TM6) to the inactive conformation, as determined from tryptophan-induced quenching studies. Accelerating Schiff base hydrolysis and subsequent ATR dissociation, either by addition of hydroxylamine or introduction of mutations, further increased the time lag between ATR release and TM6 movement. These observations show that rhodopsin can bind its agonist in equilibrium like a traditional GPCR, provide evidence that an active GPCR conformation can persist even after agonist release, and raise the possibility of targeting this key photoreceptor protein by traditional pharmaceutical-based treatments.T he superfamily of G protein-coupled receptors (GPCRs) is one of the largest targets of pharmaceutical drugs in the human genome. Classically, GPCR signaling occurs when a diffusible ligand (such as a drug) binds to the receptor and stabilizes conformations that can couple with and activate intracellular proteins. Our understanding of this process has built on the classical "ternary complex" model of receptor-ligand-G protein interaction (1), a model that, with revisions, has continued to guide our knowledge of how this critical event occurs.However, this paradigm has faced problems when applied to rhodopsin, the dim-light visual receptor. Rhodopsin is kept in an "off" state by a covalently bound inverse agonist, 11-cis retinal (11CR). Light converts the 11CR to an agonist, all-trans retinal (ATR), which enables the receptor to activate its G protein, transducin (G t ) (2, 3). The active receptor, metarhodopsin II (MII), continues signaling until the Schiff base linking ATR to the receptor is hydrolyzed, resulting in the release of ATR and the decay of MII into an inactive apoprotein, opsin (4, 5). Binding of a new 11CR to opsin reforms the dark state (DS), enabling another round of photon detection (6).Due to this unusual light-activated, covalently bound ligand, rhodopsin has usually been considered "different" from the larger superfamily of diffusible ligand-binding GPCRs. However, we recently discovered that rhodopsin behaves more like a traditional ligand-binding GPCR than previously thought (7). Our expe...

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“…3.1). Recently, a combination of methods was used to demonstrate that mouse Müller cells were responsible for an early rapid phase of mouse cone visual pigment regeneration whereas 11-cis-retinal from RPE was responsible for a slower phase (Kefalov 2012;Wang and Kefalov 2011).…”

Section: Description Of the Cone Visual Cyclementioning

confidence: 99%

Regeneration of 11-cis-Retinal in Visual Systems with Monostable and Bistable Visual Pigments

Saari

2014

Vertebrate Photoreceptors

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In this chapter, the biochemistry of visual pigment regeneration in vertebrates is discussed and comparisons are made with regeneration in selected invertebrate systems. There are clear differences in the mechanisms of regeneration of 11-cis-retinoid between retinas that rely on rhabdomeric and ciliary visual pigments. Those pigments that employ c-opsins rely on a dark, enzymatically catalyzed isomerization process. Those that employ r-opsins rely on photoreversibility of a stable meta state of the visual pigment and an independent photoisomerase. Outside the vertebrate retina, no dark isomerase has been characterized except for isomerooxygenase (NinaB), which is involved in de novo generation of chromophore from carotenoids and xanthophylls in Drosophila. Similarities in reaction types and the use of chaperones in both ciliary and rhabdomeric visual systems are largely dictated by the chemical properties of the retinoid chromophore. The toxicity of retinal and its potential for oxidation and generation of other signaling molecules (retinoic acids in vertebrates) require that chaperones bind and sequester the retinoid and that dehydrogenases are available to reduce it to the less toxic retinol. The limited solubility of retinoids requires chaperones to bind and protect the retinoids during transit between cellular and extracellular compartments. Finally, the energy requirement for 11-cis-retinoid production from all-trans-precursors requires that the reaction take place at the oxidation level of retinol, where a cleavable, energy-yielding bond can be generated and coupled with isomerization or via photoisomerization where the energy of light can be harnessed.

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Rod and Cone Visual Pigments and Phototransduction through Pharmacological, Genetic, and Physiological Approaches

Cited by 82 publications

References 90 publications

Mechanism for Selective Synaptic Wiring of Rod Photoreceptors into the Retinal Circuitry and Its Role in Vision

Mechanism for Selective Synaptic Wiring of Rod Photoreceptors into the Retinal Circuitry and Its Role in Vision

Decay of an active GPCR: Conformational dynamics govern agonist rebinding and persistence of an active, yet empty, receptor state

Regeneration of 11-cis-Retinal in Visual Systems with Monostable and Bistable Visual Pigments

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