Higher-Order Architecture of Rhodopsin in Intact Photoreceptors and Its Implication for Phototransduction Kinetics

Gunkel, Monika; Schöneberg, Johannes; Alkhaldi, Weaam; Irsen, Stephan; Noé, Frank; Kaupp, U. Benjamin; Al‐Amoudi, Ashraf

doi:10.1016/j.str.2015.01.015

Cited by 108 publications

(150 citation statements)

References 71 publications

(98 reference statements)

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“…Indeed, the possible existence of higher-order visual pigment oligomerization in the ROS has been suggested by experiments involving cross-linkers (this work and refs. 24 and 37) and cryoelectron tomography (38). Separately, visual pigment dimerization has interesting implications for mouse cones because they coexpress M and S pigments in the same cell, with an M/S pigment ratio dependent on cell location in the retina (39); thus, conceivably, M and S pigment homodimers as well as M/S pigment heterodimers may coexist in a given mouse cone.…”

Section: Discussionmentioning

confidence: 99%

Dimerization of visual pigments in vivo

Zhang

Cao

Kumar

et al. 2016

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

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It is a deeply engrained notion that the visual pigment rhodopsin signals light as a monomer, even though many G protein-coupled receptors are now known to exist and function as dimers. Nonetheless, recent studies (albeit all in vitro) have suggested that rhodopsin and its chromophore-free apoprotein, R-opsin, may indeed exist as a homodimer in rod disk membranes. Given the overwhelmingly strong historical context, the crucial remaining question, therefore, is whether pigment dimerization truly exists naturally and what function this dimerization may serve. We addressed this question in vivo with a unique mouse line (S-opsin + Lrat −/− ) expressing, transgenically, short-wavelength-sensitive cone opsin (S-opsin) in rods and also lacking chromophore to exploit the fact that cone opsins, but not R-opsin, require chromophore for proper folding and trafficking to the photoreceptor's outer segment. In R-opsin's absence, S-opsin in these transgenic rods without chromophore was mislocalized; in R-opsin's presence, however, S-opsin trafficked normally to the rod outer segment and produced functional S-pigment upon subsequent chromophore restoration. Introducing a competing R-opsin transmembrane helix H1 or helix H8 peptide, but not helix H4 or helix H5 peptide, into these transgenic rods caused mislocalization of R-opsin and S-opsin to the perinuclear endoplasmic reticulum. Importantly, a similar peptidecompetition effect was observed even in WT rods. Our work provides convincing evidence for visual pigment dimerization in vivo under physiological conditions and for its role in pigment maturation and targeting. Our work raises new questions regarding a potential mechanistic role of dimerization in rhodopsin signaling.rhodopsin | cone opsin | dimerization | protein trafficking R hodopsin and cone pigments mediate scotopic and photopic vision, respectively. They consist of opsin, the apo-protein, and 11-cis-retinal, a vitamin A-based chromophore. Light absorption by 11-cis-retinal triggers a conformational change in opsin, which in turn initiates a G protein-coupled receptor (GPCR) signaling pathway to lead to vision. Indeed, rhodopsin signaling is a prominent prototypical GPCR pathway from which a huge quantity of mechanistic details about such signaling in general has emerged. All along, it is a dogma that rhodopsin exists and functions as a monomer (1-6). About a decade ago, evidence began to emerge that rhodopsin may exist as a dimer, based on atomic force microscopy and cross-linking experiments performed on rod outersegment (ROS) disk membranes (7-9). However, this concept remains highly controversial because of the lack of in vivo evidence and also is puzzling because, unlike many GPCRs, monomeric rhodopsin is fully functional with respect to coupling to G protein (2, 4-6, 10) and to interactions with rhodopsin kinase and arrestin (11,12). In vivo evidence, albeit of paramount importance, is also challenging, because rhodopsin always exists as a single isoform in rod photoreceptors, thus making homomeric, higher-or...

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Section: Discussionmentioning

confidence: 99%

Dimerization of visual pigments in vivo

Zhang

Cao

Kumar

et al. 2016

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

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“…The flagellum harbours about 300,000 GC copies at a density of 9,500 GC molecules/μm 2 [4]. In fact, the GC rivals with rhodopsin in photoreceptors (20,000-45,000 rhodopsin molecules/μm 2 ) [40,41] as one of the most densely packed membrane receptors. What determines the precision by which sperm count molecules?…”

Section: The Chemoattractant Receptormentioning

confidence: 99%

Sperm as microswimmers – navigation and sensing at the physical limit

Kaupp

Álvarez

2016

Eur. Phys. J. Spec. Top.

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Abstract. Many cells and microorganisms have evolved a motility apparatus to explore their surroundings. For guidance, these biological microswimmers rely on physical and chemical cues that are transduced by cellular pathways into directed movement -a process called taxis. Only few biological microswimmers have been studied as detailed as sperm from sea urchins. Sperm and eggs are released into the seawater. To enhance the chances of fertilization, eggs release chemical factors -called chemoattractants -that establish a chemical gradient and, thereby, guide sperm to the egg. Sea urchin sperm constitute a unique model system for understanding cell navigation at every level: from molecules to cell behaviours. We will outline the chemotactic signalling pathway of sperm from the sea urchin Arbacia punctulata and discuss how signalling controls navigation in a chemical gradient. Finally, we discuss recent insights into sperm chemotaxis in three dimensions (3D).

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“…A possible scenario would be that one of the binding partners is held in a supramolecular structure, from or in which it is slowly made available for interaction (Schöneberg et al, 2014). This is reminiscent of recent work on rhodopsin, which has resulted in dramatically different simulated activation rates of G t , depending on the localization of the activating R* within or outside rows of dimers of the receptor (Gunkel et al, 2015). Intriguingly, the high speed of G-protein activation in vitro (Heck and Hofmann, 2001) would only be true for a limited number of G-proteins, which are localized within the oligomer containing the R*.…”

Section: Temporal Aspects-kinetics Along the Signaling Chainmentioning

confidence: 99%

Spatial and Temporal Aspects of Signaling by G-Protein–Coupled Receptors

Lohse

Hofmann

2015

Mol Pharmacol

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Signaling by G-protein-coupled receptors is often considered a uniform process, whereby a homogeneously activated proportion of randomly distributed receptors are activated under equilibrium conditions and produce homogeneous, steady-state intracellular signals. While this may be the case in some biologic systems, the example of rhodopsin with its strictly local singlequantum mode of function shows that homogeneity in space and time cannot be a general property of G-protein-coupled systems. Recent work has now revealed many other systems where such simplicity does not prevail. Instead, a plethora of mechanisms allows much more complex patterns of receptor activation and signaling: different mechanisms of proteinprotein interaction; temporal changes under nonequilibrium conditions; localized receptor activation; and localized second messenger generation and degradation-all of which shape receptor-generated signals and permit the creation of multiple signal types. Here, we review the evidence for such pleiotropic receptor signaling in space and time.

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Higher-Order Architecture of Rhodopsin in Intact Photoreceptors and Its Implication for Phototransduction Kinetics

Cited by 108 publications

References 71 publications

Dimerization of visual pigments in vivo

Dimerization of visual pigments in vivo

Sperm as microswimmers – navigation and sensing at the physical limit

Spatial and Temporal Aspects of Signaling by G-Protein–Coupled Receptors

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