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Review
. 2021 Sep;473(9):1361-1376.
doi: 10.1007/s00424-021-02522-5. Epub 2021 Feb 16.

Supramolecular organization of rhodopsin in rod photoreceptor cell membranes

Paul S-H Park  1
Affiliations
Review

Supramolecular organization of rhodopsin in rod photoreceptor cell membranes

Paul S-H Park. Pflugers Arch. 2021 Sep.

Abstract

Rhodopsin is the light receptor in rod photoreceptor cells that initiates scotopic vision. Studies on the light receptor span well over a century, yet questions about the organization of rhodopsin within the photoreceptor cell membrane still persist and a consensus view on the topic is still elusive. Rhodopsin has been intensely studied for quite some time, and there is a wealth of information to draw from to formulate an organizational picture of the receptor in native membranes. Early experimental evidence in apparent support for a monomeric arrangement of rhodopsin in rod photoreceptor cell membranes is contrasted and reconciled with more recent visual evidence in support of a supramolecular organization of rhodopsin. What is known so far about the determinants of forming a supramolecular structure and possible functional roles for such an organization are also discussed. Many details are still missing on the structural and functional properties of the supramolecular organization of rhodopsin in rod photoreceptor cell membranes. The emerging picture presented here can serve as a springboard towards a more in-depth understanding of the topic.

Keywords: G protein-coupled receptor; Membrane protein; Nanodomain; Photoreceptor cell; Phototransduction; Quaternary structure.

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Conflict of interest statement

Conflict of Interest

The author declares that they have no conflicts of interest.

Figures

Figure 1.
Figure 1.
Rod photoreceptor cell. Rod photoreceptor cells are compartmentalized into an outer segment and inner segment. The outer segment contains stacks of membranous discs. Rhodopsin (red) is packed into the disc membranes. Figure reprinted from [115], with permission from Elsevier.
Figure 2.
Figure 2.
Rhodopsin activity. Rhodopsin (red) is activated when 11-cis retinal is isomerized to all-trans retinal by light. The active state of rhodopsin, MII (yellow), engages and activates the heterotrimeric G protein transducin (green). Rhodopsin is deactivated upon phosphorylation by rhodopsin kinase and binding arrestin (blue). All-trans retinal is released from rhodopsin, leaving the apoprotein opsin (grey). Opsin must be regenerated with 11-cis retinal to reform rhodopsin. Figure adapted from [105], with permission from Elsevier.
Figure 3.
Figure 3.
Timeline highlighting major advancements in our molecular and structural understanding about rhodopsin. Figure adapted from [62], with permission from Elsevier.
Figure 4.
Figure 4.
Different supramolecular arrangements of rhodopsin in ROS disc membranes observed by AFM and cryo-ET. A. Rhodopsin arranged in rows of dimers of variable lengths forming a densely packed paracrystalline lattice. B. Rhodopsin arranged in rows of dimers of variable lengths forming nanodomains. C. Rhodopsin arranged in rows of dimers forming nanodomains mostly of uniform size and aligned parallel to the incisure.
Figure 5.
Figure 5.
Distribution of rhodopsin oligomeric forms. A. A chemical equilibria description of rhodopsin oligomerization. Rhodopsin (R) forms oligomers of various sizes (denoted by superscript). The concentration of rhodopsin and the equilibrium constants will dictate the complement of oligomeric forms of rhodopsin present in the membrane. B. Histogram of different sizes of rhodopsin oligomers detected by AFM in native ROS disc membranes. Data showing the distribution of nanodomain sizes in [115] was converted to the number of rhodopsin molecules in an oligomeric complex by presuming each rhodopsin molecule occupies 14 nm2 of space, as described previously in [149]. The distribution of rhodopsin oligomeric sizes in ROS disc membranes is shown for mice housed under constant dark (black) or constant light (red) conditions for 10 days. The inset shows a zoomed in view of the histogram for oligomeric sizes greater than 70 rhodopsin molecules. The histograms were fit with a log Gaussian function.
Figure 6.
Figure 6.
Rhodopsin dimer structures. A. Rhodopsin dimer structure derived from AFM data [76](PDB: 1N3M). B. A cryo-EM rhodopsin dimer structure [157](PDB: 6OFJ). TM4 and TM5 are colored blue and TM1 and H8 are colored red.
Figure 7.
Figure 7.
FRET analysis of wild-type (WT) and F45L mutant rhodopsin. FRET experiments were conducted in HEK293 cells coexpressing mTurquoise2 (mTq2)- and yellow fluorescent protein (YFP)-tagged human WT rhodopsin or mTq2- and YFP-tagged human F45L mutant rhodopsin, as described previously [48]. DNA constructs for WT rhodopsin are described in [47]. The F45L mutation was introduced into the sequence for WT rhodopsin adapting procedures in the QuickChange II Site-Directed Mutagenesis Kit (Agilent Technologies, Santa Clara, CA), as described previously for other point mutations [47]. A, B. Fluorescence emission spectra were collected after excitation at 425 nm of cells coexpressing mTq2- and YFP-tagged WT rhodopsin (A) or mTq2- and YFP-tagged F45L mutant rhodopsin (B). Fluorescence emission spectra were obtained from untreated cells, cells treated with 1.3 mM n-dodecyl-β-D-maltoside (DM) for 5 minutes and then 3.3 mM SDS for 5 minutes. The FRET efficiency (E) was computed by measuring the dequenching of fluorescence emission from mTq2 at 476 nm (Em476). DM-sensitive FRET, which corresponds to rhodopsin oligomers [48], was computed as follows: E = (Em476DM-treated – Em476untreated))/Em476SDS-treated. The example spectra were obtained at an acceptor (YFP) to donor (mTq2) ratio (A:D ratio) of 2. C. DM-sensitive FRET efficiencies were computed at different A:D ratios to generate FRET curves. The data were fit by non-linear regression to a rectangular hyperbolic function using Prism 7 (GraphPad Software, San Diego, CA). FRET curves for WT and F45L mutant rhodopsin were similar, indicating both forms of the receptor similarly form oligomers.
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