Rhodopsin

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Rhodopsin, also known as visual purple, is a protein encoded by the RHO gene<ref name="NCBI">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and a G-protein-coupled receptor (GPCR). It is a light-sensitive receptor protein that triggers visual phototransduction in rod cells. Rhodopsin mediates dim light vision and thus is extremely sensitive to light.<ref name="Litmann_1996">Template:Cite book</ref> When rhodopsin is exposed to light, it immediately photobleaches. In humans, it is fully regenerated in about 30 minutes, after which the rods are more sensitive.<ref name="Stuart_1996">Template:Cite book</ref> Defects in the rhodopsin gene cause eye diseases such as retinitis pigmentosa and congenital stationary night blindness.

HistoryEdit

Rhodopsin was discovered by Franz Christian Boll in 1876.<ref>Template:Cite book</ref><ref name="Giese2013">Template:Cite book</ref><ref>Template:Cite journal</ref> The name rhodopsin derives from Ancient Greek Template:Wikt-lang (Template:Grc-transl) for "rose", due to its pinkish color, and Template:Wikt-lang (Template:Grc-transl) for "sight".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It was coined in 1878 by the German physiologist Wilhelm Friedrich Kühne (1837–1900).<ref>See:

Merriam-Webster Online Dictionary: Rhodopsin: History and Etymology for rhodopsin
Template:Cite journal From p. 181: "Was den Sehpurpur im Dunkel ändert, pflegt es z. Th. [= zum Theil] in derselben Weise zu thun, wie das Licht, d.h. erst eine gelbe Materie, dann farblose Substanz hervorzubringen. Der Kürze wegen und um dem Auslande unsere Bezeichnungen zugänglich zu machen, kann man sagen, Rhodopsin werde erst in Xanthopsin, dieses in Leukopsin zersetzt." (That which alters visual purple in the dark usually acts to some extent in the same way as light, that is, first producing a yellow material, then a colorless substance. For the sake of brevity, and in order to make our designations more accessible to foreigners, we can say that rhodopsin is first degraded into xanthopsin [- visual yellow], and [then] this is degraded into leucopsin [- visual white].)</ref><ref>Template:Cite journal</ref>

When George Wald discovered that rhodopsin is a holoprotein, consisting of retinal and an apoprotein, he called it opsin, which today would be described more narrowly as apo-rhodopsin.<ref>Template:Cite journal</ref> Today, the term opsin refers more broadly to the class of G-protein-coupled receptors that bind retinal and as a result become a light-sensitive photoreceptor, including all closely related proteins.<ref name="Terakita2005" /><ref name=Guehmann2022 /><ref name=Hofmann2022>Template:Cite journal</ref>Template:Efn When Wald and colleagues later isolated iodopsin from chicken retinas, thereby discovering the first known cone opsin, they called apo-iodopsin photopsin (for its relation to photopic vision) and apo-rhodopsin scotopsin (for its use in scotopic vision).<ref>Template:Cite journal</ref>

GeneralEdit

Rhodopsin is a protein found in the outer segment discs of rod cells. It mediates scotopic vision, which is monochromatic vision in dim light.<ref name="Stuart_1996"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Rhodopsin most strongly absorbs green-blue light (~500 nm)<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and appears therefore reddish-purple, hence the archaic term "visual purple".

Several closely related opsins differ only in a few amino acids and in the wavelengths of light that they absorb most strongly. Humans have, including rhodopsin, nine opsins,<ref name="Terakita2005">Template:Cite journal</ref> as well as cryptochrome (light-sensitive, but not an opsin).<ref name="FoleyGegear2011">Template:Cite journal</ref>

StructureEdit

File:Bovine rhodopsin.png

Cattle rhodopsin

Rhodopsin, like other opsins, is a G-protein-coupled receptor (GPCR).<ref name=Casey1988>Template:Cite journal</ref><ref name=Attwood1994>Template:Cite journal</ref> GPCRs are chemoreceptors that embed in the lipid bilayer of the cell membranes and have seven transmembrane domains forming a binding pocket for a ligand.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The ligand for rhodopsin is the vitamin A-based chromophore 11-cis-retinal,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> which lies horizontally to the cell membrane<ref name=Palczewski2000>Template:Cite journal</ref> and is covalently bound to a lysine residue (lys296)<ref name=Bownds1965>Template:Cite journal</ref> in the seventh transmembrane domain<ref>Template:Cite journal</ref><ref name=Palczewski2000 /> through a Schiff-base.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> However, 11-cis-retinal only blocks the binding pocket and does not activate rhodopsin. It is only activated when 11-cis-retinal absorbs a photon of light and isomerizes to all-trans-retinal,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> the receptor activating form,<ref name=Choe2011>Template:Cite journal</ref><ref name=Wald1968>Template:Cite journal</ref> causing conformal changes in rhodopsin (bleaching),<ref name=Choe2011 /> which activate a phototransduction cascade.<ref name = "Terakita_2012">Template:Cite journal</ref> Thus, a chemoreceptor is converted to a light or photo(n)receptor.<ref name=Guehmann2022>Template:Cite journal File:CC-BY icon.svg Material was copied and adapted from this source, which is available under a Creative Commons Attribution 4.0 International License.</ref>

The retinal binding lysine is conserved in almost all opsins, only a few opsins having lost it during evolution.<ref name=Guehmann2022 /> Opsins without the lysine are not light sensitive,<ref name=Katana2019>Template:Cite journal</ref><ref name=Leung2020>Template:Cite journal</ref><ref>Template:Cite journal</ref> including rhodopsin. Rhodopsin is made constitutively (continuously) active by some of those mutations even without light.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Pharmacology & Therapeutics of Cons">Template:Cite book</ref> Also wild-type rhodopsin is constitutively active, if no 11-cis-retinal is bound, but much less.<ref>Template:Cite journal</ref> Therefore 11-cis-retinal is an inverse agonist. Such mutations are one cause of autosomal dominant retinitis pigmentosa.<ref name="Pharmacology & Therapeutics of Cons"/> Artificially, the retinal binding lysine can be shifted to other positions, even into other transmembrane domains, without changing the activity.<ref>Template:Cite journal</ref>

The rhodopsin of cattle has 348 amino acids, the retinal binding lysine being Lys296. It was the first opsin whose amino acid sequence<ref name=Ovchinnikov1982>Template:Cite journal</ref> and 3D-structure were determined.<ref name=Palczewski2000 /> Its structure has been studied in detail by x-ray crystallography on rhodopsin crystals.<ref name="Gulati2017">Template:Cite journal</ref> Several models (e.g., the bicycle-pedal mechanism, hula-twist mechanism) attempt to explain how the retinal group can change its conformation without clashing with the enveloping rhodopsin protein pocket.<ref name="pmid16586416">Template:Cite journal</ref><ref name="pmid16729349">Template:Cite journal</ref><ref name="pmid17691730">Template:Cite journal</ref> Recent data support that rhodopsin is a functional monomer, instead of a dimer, which was the paradigm of G-protein-coupled receptors for many years.<ref name="pmid15996094">Template:Cite journal</ref>

Within its native membrane, rhodopsin is found at a high density facilitating its ability to capture photons. Due to its dense packing within the membrane, there is a higher chance of rhodopsin capturing photons. However, the high density also is a disadvantage when it comes to G protein signaling because the needed diffusion becomes more difficult in a crowded membrane that is packed with rhodopsin.<ref>Template:Cite journal</ref>

PhototransductionEdit

File:Visual cycle.svg

The visual cycle follows the renewal of the retinal chromophore. It runs in parallel to the phototransduction pathway.

Rhodopsin is an essential G-protein coupled receptor in phototransduction.

ActivationEdit

In rhodopsin, the aldehyde group of retinal is covalently linked to the amino group of a lysine residue on the protein in a protonated Schiff base (-NH⁺=CH-).<ref name=Bownds1965 /> When rhodopsin absorbs light, its retinal cofactor isomerizes from the 11-cis to the all-trans configuration, and the protein subsequently undergoes a series of relaxations to accommodate the altered shape of the isomerized cofactor. The intermediates formed during this process were first investigated in the laboratory of George Wald, who received the Nobel prize for this research in 1967.<ref name=WaldNobelPrize>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The photoisomerization dynamics has been subsequently investigated with time-resolved IR spectroscopy and UV/Vis spectroscopy. A first photoproduct called photorhodopsin forms within 200 femtoseconds after irradiation, followed within picoseconds by a second one called bathorhodopsin with distorted all-trans bonds. This intermediate can be trapped and studied at cryogenic temperatures, and was initially referred to as prelumirhodopsin.<ref>Template:Cite journal</ref> In subsequent intermediates lumirhodopsin and metarhodopsin I, the Schiff's base linkage to all-trans retinal remains protonated, and the protein retains its reddish color. The critical change that initiates the neuronal excitation involves the conversion of metarhodopsin I to metarhodopsin II, which is associated with deprotonation of the Schiff's base and change in color from red to yellow.<ref>Template:Cite journal</ref>

Phototransduction cascadeEdit

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The product of light activation, Metarhodopsin II, initiates the visual phototransduction second messenger pathway by stimulating the G-protein transducin (G_t), resulting in the liberation of its α subunit. This GTP-bound subunit in turn activates a cGMP phosphodiesterase. The cGMP phosphodiesterase hydrolyzes (breaks down) cGMP, lowering its local concentration so it can no longer activate cGMP-dependent cation channels. This leads to the hyperpolarization of photoreceptor cells, changing the rate at which they release transmitters.<ref name="Hofmann_1996">Template:Cite book</ref><ref name = "Terakita_2012" />

DeactivationEdit

Meta II (metarhodopsin II) is deactivated rapidly after activating transducin by rhodopsin kinase and arrestin.<ref name="pmid12427735">Template:Cite journal</ref> Rhodopsin pigment must be regenerated for further phototransduction to occur. This means replacing all-trans-retinal with 11-cis-retinal and the decay of Meta II is crucial in this process. During the decay of Meta II, the Schiff base link that normally holds all-trans-retinal and the apoprotein opsin (aporhodopsin) is hydrolyzed and becomes Meta III. In the rod outer segment, Meta III decays into separate all-trans-retinal and opsin.<ref name="pmid12427735"/> A second product of Meta II decay is an all-trans-retinal opsin complex in which the all-trans-retinal has been translocated to second binding sites. Whether the Meta II decay runs into Meta III or the all-trans-retinal opsin complex seems to depend on the pH of the reaction. Higher pH tends to drive the decay reaction towards Meta III.<ref name="pmid12427735"/>

Diseases of the retinaEdit

Mutations in the rhodopsin gene contribute majorly to various diseases of the retina such as retinitis pigmentosa. In general, the defect rhodopsin aggregates with ubiquitin in inclusion bodies, disrupts the intermediate filament network, and impairs the ability of the cell to degrade non-functioning proteins, which leads to photoreceptor apoptosis.<ref name="pmid12082151">Template:Cite journal</ref> Other mutations on rhodopsin lead to X-linked congenital stationary night blindness, mainly due to constitutive activation, when the mutations occur around the chromophore binding pocket of rhodopsin.<ref name="pmid15823756">Template:Cite journal</ref> Several other pathological states relating to rhodopsin have been discovered including poor post-Golgi trafficking, dysregulative activation, rod outer segment instability and arrestin binding.<ref name="pmid15823756"/>