Rhodopsin: Difference between revisions

Revision as of 07:39, 8 August 2024

Introduction

Rhodopsin

Rhodopsin, a homodimeric protein, is a highly characterized G protein-coupled receptor found in membranous disks of the outer segments of rod and cone cells, though rhodopsin is more concentrated in rod cells which are sensitive to light but cannot discriminate colors. Rhodopsin is part of the superfamily of G protein-coupled receptors that mediate responses to visual, olfactory, hormonal, and neurotransmitter signals among others^[1]. Rhodopsin is involved in visual signal transduction and the visual system in classic G protein-coupled receptor mechanisms^[2].

Sodium pump rhodopsin transports Na+ and H+ depending on ionic conditions^[3].
Chloride pump rhodopsin transports Cl- into cells^[4].
Metarhodopsin II is a rhodopsin intermediate in which the retinal Schiff base is still intact but deprotonated^[5].
Bathorhodopsin and Lumirhodopsin are rhodopsin complexes with metastable intermediates of retinal^[6],^[7].
Halorhodopsin is a light-driven chloride pump rhodopsin that can be used to silence neural activity via light^[8].
Archaerhodopsin is a light-driven proton pump^[9].
Proteorhodopsin is the most abundant proton pump^[10].
Xanthorhodopsin contains a cartenoid/retinal complex in which the carotenoid serves as light-harvesting antennais^[11].

G Protein-Coupled Receptors

Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signaling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus^[12]. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well ^[2]. Given that the the seven transmembrane domain of rhodopsin was the first solved crystal structure and that very few have been determined for other members of the G protein-coupled receptor superfamily, rhodopsin often serves as a reference for the structure and function relationship for other G protein-coupled receptors^[12]^[13]. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case transducin (Transducin), which interacts with the cytoplasmic loops of the receptor^[14]. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. Additionally, most other members of the superfamily use small ligands as inducers, whereas rhodopsin uses light as the inducer for activation^[12].

Structure

Rhodopsin Architecture

Rhodopsin consists of seven mostly α-helical transmembrane domains (H1-H7) linked sequentially by extracellular and cytoplasmic loops (E1-E3 and C1-C3 respectively), with the extracellular amino-terminal tail and the cytoplasmic carboxyl-terminal tail^[2]. Four of the helices are tilted and three of the helices are approximately perpendicular to the membrane plane^[15]. There is notable interaction between the four extracellular domains, but only a few associations are observed with the cytoplasmic domains^[16]. Helix 7 is close to being elongated around the Lysine 296 retinal attachment site, and also contains the residues Proline 291 and Proline 303, with Proline 303 being part of a conserved motif^[16]. Near the retinal region, there is a β4 strand (Serine 186-Cysteine 187-Glycine 188-Isoleucine 189) within the Extracellular Helix 2 that runs almost parallel to the chromophore held in place and is stabilized by the essential conserved disulfide bond between Cysteine 110 and Cysteine 187. This loop also potentially contacts the chromophore through Glutamine 181 and Tyrosine 191^[2].

Water molecules are observed to be located in the extracellular domains of rhodopsin; specifically, the water molecules around the second extracellular loop between Helix 4 and 5 solvate the loop when the loop interacts with the retinal chromophore and possibly contribute to its flexibility should rearrangement occur^[17].

There is the presence of a cationic amphipathic Helix 8, known as the fourth cytoplasmic loop, that spans from Asparagine 310 to Cysteine 323 and is formed from the C-terminal tail anchoring to the membrane by

Cysteine 322 and Cysteine 323, which are palmitoylated. This helix runs approximately parallel to the cytoplasmic surface and is involved in Gtγ binding^[16], as well as the modulation of rhodopsin-transducin interactions and rhodopsin-phospholipid interactions^[2].

A metal zinc ion bridge chelated by histidine side-chains and connected to the cytoplasmic ends of Helix 3 and 6 is observed to prevent receptor activation. This perhaps indicates that separation of these cytoplasmic ends would contribute to rhodopsin activation^[14].

The structure of rhodopsin may provide stability to the important Schiff base linkage with the retinal by affecting its hydrolysis, limiting its interactions with solvent, and inhibiting its release when hydrolyzed, thus encouraging rebinding of the Schiff base linkage^[18].

Retinal Chromophore of Rhodopsin

Rhodopsin consists of an opsin apoprotein and a 11-cis retinylidene chromophore in its active site. Rhodopsin is bound covalently to the 11-cis retinal, the chromophore or "ligand," (shown in yellow) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer^[19]. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer ^[2]. The retinal is attached in the active site of rhodopsin through a protonated Schiff base (an N-substituted imine) bond to the ε-amino group of Lysine 296 residue (shown in green) on the C-terminal Helix 7, with this linkage creating a positive charge on the chromophore ^[15]. The protonated Schiff base of rhodopsin is stabilized through Glutamine 113 residue electrostatic interaction with the counterion, holding the inactive rhodopsin in its state^[12].

As this ligand is bound in the 12-s-trans conformation, there arises the non-bonding interactions between the C-13 methyl group and C-10 hydrogen that contribute to non-planarity. This leads to the ability of the chromophore polyene tail to undergo fast photoisomerization around the C-11=C-12 double bond during light-induced activation^[20]. Also, it is found that the C-11=C-12 double bond is pre-twisted in the ground state of rhodopsin, which is partly attributed to the C20 methyl group attached to C13 through interaction with Tryptophan 265. This pre-twist may give insight on the features of isomerization about this bond upon light activation^[17].

Somewhat enclosing this chromophore is a retinal binding pocket partially formed by the N-terminal domain overlaying the extracellular turns including the second extracellular loop, which folds into the molecular center^[21].

Function

Visual Signal Transduction

Photoisomerization of 11-cis Retinal

The 11-cis retinal (retinylidene) Schiff base functions as an inverse agonist and is prominently involved in the activation of rhodopsin. The primary step in rhodopsin photoactivation occurs in the photoisomerization of rhodopsin, as light energy absorbed from a photon is converted into chemical energy. As a photon is absorbed by the retina, the 11-cis retinylidene ligand is switched into an all-trans retinal configuration^[20]. In this extremely efficient <200 fs process, the protein-binding pocket, initially fitted to accommodate the 11-cis conformation of the chromophore, is preserved, which restrains the relaxation of the chromophore. The strained relaxation of conformational energy changes the protein state into the active form^[20].

Adjustment and Thermal Relaxation of the Protein

Upon activation, movement and slight adjustment of helices are observed, with the inner faces of Helix 2, 3, 6 and 7 becoming more exposed^[14]. As Helices 3 and 6 move outward, the binding site for transducin is more accessible as there is opening between cytoplasmic loops^[19]. Following activation, a slower thermal relaxation process occurs. This involves conformational changes in the retinal and opsin to result in fully active Metarhodopsin II^[21].

Formation of the Metarhodopsin II State

Rhodopsin forms to Metarhodopsin II, the intermediate signaling state where interaction occurs with the G protein. This millisecond process is accompanied by movement in the helices, uptake of protons in the cytoplasm, and the breakage of the salt bridge between Glutamine 113 and the protonated Schiff base. The Schiff base deprotonates and the proton is transferred to the Glutamine 113 counterion, destabilizing the ground state ^[16]. As well, this Metarhodopsin II formation may be dependent on the protonation too of the conserved Glutamine 134 that forms a salt bridge with Arginine 135, thus destabilizing the constraint on Arginine 135^[16].

There is positive enthalpy associated with the formation of Metarhodopsin II. This formation of the active state, also linked with the increase in entropy, is suggested to release the constraints in the helices and expose the cytoplasmic binding sites^[16]. An important part of this process includes the 9-methyl group of retinal, which is suggested to provide a scaffold for proton transfers essential for the formation of the active state^[16].

Signaling Cascade and Polarization of the Cell Membrane

The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasmic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit^[21]. Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates cGMP-specific phosphodiesterase by binding and removing its inhibitory subunit^[22]. The cGMP phosphodiesterase is an integral protein of the retina with its active site on the cytoplasmic side of the disk. Its inhibitory subunit tightly binds to it in the dark and suppresses its activity. The now activated phosphodiesterase degrades many molecules of cGMP, efficiently decreasing the concentration of cGMP^[22]. This results in the closing of the cGMP-gated cation channels in the plasma membrane of the outer segment. The cell hyperpolarizes due to the decrease in the influx of sodium and calcium ions, which results in the decrease of the release of glutamate into the synaptic cleft. This electric signal of this hyperpolarization is sent to the brain through ranks of interconnecting neurons and then through the optic nerve^[21].

Visual Signal Termination

Recovery of the Pre-stimulus State

In the event of a decrease in light intensity, GTP is hydrolyzed and the α-subunit of transducin reassociates with the βγ subunits, releasing the inhibitory subunit of phosphodiesterase. This subunit reassociates with phosphodiesterase and inhibits its activity^[22]. The concentration of cGMP is returned to the “dark” state by the conversion of GTP to cGMP by guanylyl cyclase, activated through the efflux of calcium ions through the sodium/calcium ion exchanger. The reduction in the concentration of calcium ions also inhibits phosphodiesterase activity. Both actions reopen the cation channels and restore the system to pre-stimulus state^[22].

Phosphorylation and Deactivation of Rhodopsin

Rhodopsin kinase phosphorylates rhodopsin and arrestin binds to the phosphorylated domain of rhodopsin, preventing further signal transduction from Metarhodopsin II of activated rhodopsin and transducin^[18]. It phosphorylates both Metarhodopsin II and cone opsins. The majority of the phosphorylation sites are in the cytoplasmic C-terminal region of rhodopsin with seven hydroxy-amino acids. The most favoured amino acids are Serine 338, Serine 343, Serine 334, Threonine 335 and Threonine 336^[23], and these residues form an arrangement in rhodopsin that do not appear to be exposed to the solvent. Interactions with the C-terminal tail and a portion of the Cytoplasmic loop 3 appear to be broken for the phosphorylation of the hydroxyl groups^[16]. For the next cycle of activation of rhodopsin, rhodopsin has to be dephosphorylated, and have the all-trans retinal replaced with the 11-cis retinal^[19].

Altogether, the different states of rhodopsin which include the short-lived, photo-rhodopsin, batho-rhodopsin, and lumi-rhodopsin, and longer-lived meta-rhodopsins give information about the structural status of the molecule during activation^[16].

Opsin

Topology Overview

The overall dimeric structure of opsin is similar to rhodopsin, with seven transmembrane helices linked by three extracellular loops and three cytoplasmic loops and a cytoplasmic Helix 8. The small differences between the topology of the two proteins include a short helical turn in the cytoplasmic loop 1 in opsin, 1.5-2.5 helical turns longer in Helix 5 for opsin in comparison to rhodopsin, and a large outward tilt of Helix 6 of opsin^[24]. Also, in contrast to rhodopsin, opsin has two openings of the retinal-binding pocket; one of the openings is between Helix 1 and Helix 7, and the other opening is between the extracellular ends of Helix 5 and 6. This opening is formed by the residues Isoleucine 205 and Phenylalanine 208 in Helix 5, and by the residues Phenylalanine 273 and Phenylalanine 276 in Helix 6^[24]. The two openings suggest different sites of retinal entrance and exit in retinal channeling^[24].

Activity

The ability of opsin to activate transducin is modulated by both 11-cis retinal and the all-trans retinal; the 11-cis retinal reduces its activity while the all-trans retinal enhances it through non-covalent interactions ^[25]. This may give insight on the ability of all-trans retinal, in combination with opsin, to alter the photoreceptor sensitivities^[25].

Colour Vision

Opsins are also photoreceptor proteins and are concentrated in cone cells, cells that are less sensitive to light but can discriminate colours. Opsins are slightly different light receptors than rhodopsin in that they can detect light from different spectrums and distinguish between their wavelengths. The ability to differentiate between colours is related to the three types of cone cells, each using one of the three related opsin photoreceptors^[22].

† PDB structure used in this section: 3cap

3D structures of rhodopsin

Rhodopsin 3D structures

↑ Hornak V, Ahuja S, Eilers M, Goncalves JA, Sheves M, Reeves PJ, Smith SO. Light activation of rhodopsin: insights from molecular dynamics simulations guided by solid-state NMR distance restraints. J Mol Biol. 2010 Feb 26;396(3):510-27. Epub 2009 Dec 11. PMID:20004206 doi:10.1016/j.jmb.2009.12.003
↑ ^2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 Sakmar TP. Structure of rhodopsin and the superfamily of seven-helical receptors: the same and not the same. Curr Opin Cell Biol. 2002 Apr;14(2):189-95. PMID:11891118
↑ Tsunoda SP, Prigge M, Abe-Yoshizumi R, Inoue K, Kozaki Y, Ishizuka T, Yawo H, Yizhar O, Kandori H. Functional characterization of sodium-pumping rhodopsins with different pumping properties. PLoS One. 2017 Jul 27;12(7):e0179232. PMID:28749956 doi:10.1371/journal.pone.0179232
↑ Yun JH, Li X, Yue J, Park JH, Jin Z, Li C, Hu H, Shi Y, Pandey S, Carbajo S, Boutet S, Hunter MS, Liang M, Sierra RG, Lane TJ, Zhou L, Weierstall U, Zatsepin NA, Ohki M, Tame JRH, Park SY, Spence JCH, Zhang W, Schmidt M, Lee W, Liu H. Early-stage dynamics of chloride ion-pumping rhodopsin revealed by a femtosecond X-ray laser. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13). pii: 2020486118. doi:, 10.1073/pnas.2020486118. PMID:33753488 doi:https://dx.doi.org/10.1073/pnas.2020486118
↑ Choe HW, Kim YJ, Park JH, Morizumi T, Pai EF, Krauss N, Hofmann KP, Scheerer P, Ernst OP. Crystal structure of metarhodopsin II. Nature. 2011 Mar 9. PMID:21389988 doi:10.1038/nature09789
↑ Schapiro I, Ryazantsev MN, Frutos LM, Ferré N, Lindh R, Olivucci M. The ultrafast photoisomerizations of rhodopsin and bathorhodopsin are modulated by bond length alternation and HOOP driven electronic effects. J Am Chem Soc. 2011 Mar 16;133(10):3354-64. PMID:21341699 doi:10.1021/ja1056196
↑ Pan D, Mathies RA. Chromophore structure in lumirhodopsin and metarhodopsin I by time-resolved resonance Raman microchip spectroscopy. Biochemistry. 2001 Jul 3;40(26):7929-36. PMID:11425321 doi:10.1021/bi010670x
↑ Zhao S, Cunha C, Zhang F, Liu Q, Gloss B, Deisseroth K, Augustine GJ, Feng G. Improved expression of halorhodopsin for light-induced silencing of neuronal activity. Brain Cell Biol. 2008 Aug;36(1-4):141-54. PMID:18931914 doi:10.1007/s11068-008-9034-7
↑ Ganapathy S, Kratz S, Chen Q, Hellingwerf KJ, de Groot HJM, Rothschild KJ, de Grip WJ. Redshifted and Near-infrared Active Analog Pigments Based upon Archaerhodopsin-3. Photochem Photobiol. 2019 Jul;95(4):959-968. PMID:30860604 doi:10.1111/php.13093
↑ Bamann C, Bamberg E, Wachtveitl J, Glaubitz C. Proteorhodopsin. Biochim Biophys Acta. 2014 May;1837(5):614-25. doi: 10.1016/j.bbabio.2013.09.010., Epub 2013 Sep 20. PMID:24060527 doi:https://dx.doi.org/10.1016/j.bbabio.2013.09.010
↑ Balashov SP, Lanyi JK. Xanthorhodopsin: Proton pump with a carotenoid antenna. Cell Mol Life Sci. 2007 Sep;64(18):2323-8. PMID:17571211 doi:10.1007/s00018-007-7167-y
↑ ^12.0 ^12.1 ^12.2 ^12.3 Kristiansen K. Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function. Pharmacol Ther. 2004 Jul;103(1):21-80. PMID:15251227 doi:10.1016/j.pharmthera.2004.05.002
↑ Millar RP, Newton CL. The year in G protein-coupled receptor research. Mol Endocrinol. 2010 Jan;24(1):261-74. Epub 2009 Dec 17. PMID:20019124 doi:10.1210/me.2009-0473
↑ ^14.0 ^14.1 ^14.2 Meng EC, Bourne HR. Receptor activation: what does the rhodopsin structure tell us? Trends Pharmacol Sci. 2001 Nov;22(11):587-93. PMID:11698103
↑ ^15.0 ^15.1 Shieh T, Han M, Sakmar TP, Smith SO. The steric trigger in rhodopsin activation. J Mol Biol. 1997 Jun 13;269(3):373-84. PMID:9199406 doi:10.1006/jmbi.1997.1035
↑ ^16.0 ^16.1 ^16.2 ^16.3 ^16.4 ^16.5 ^16.6 ^16.7 ^16.8 Okada T, Ernst OP, Palczewski K, Hofmann KP. Activation of rhodopsin: new insights from structural and biochemical studies. Trends Biochem Sci. 2001 May;26(5):318-24. PMID:11343925
↑ ^17.0 ^17.1 Okada T, Sugihara M, Bondar AN, Elstner M, Entel P, Buss V. The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure. J Mol Biol. 2004 Sep 10;342(2):571-83. PMID:15327956 doi:10.1016/j.jmb.2004.07.044
↑ ^18.0 ^18.1 Janz JM, Farrens DL. Assessing structural elements that influence Schiff base stability: mutants E113Q and D190N destabilize rhodopsin through different mechanisms. Vision Res. 2003 Dec;43(28):2991-3002. PMID:14611935
↑ ^19.0 ^19.1 ^19.2 Kisselev OG. Focus on molecules: rhodopsin. Exp Eye Res. 2005 Oct;81(4):366-7. PMID:16051215 doi:10.1016/j.exer.2005.06.018
↑ ^20.0 ^20.1 ^20.2 Verhoeven MA, Bovee-Geurts PH, de Groot HJ, Lugtenburg J, DeGrip WJ. Methyl substituents at the 11 or 12 position of retinal profoundly and differentially affect photochemistry and signalling activity of rhodopsin. J Mol Biol. 2006 Oct 13;363(1):98-113. Epub 2006 Jul 28. PMID:16962138 doi:10.1016/j.jmb.2006.07.039
↑ ^21.0 ^21.1 ^21.2 ^21.3 Morris MB, Dastmalchi S, Church WB. Rhodopsin: structure, signal transduction and oligomerisation. Int J Biochem Cell Biol. 2009 Apr;41(4):721-4. Epub 2008 Aug 3. PMID:18692154 doi:10.1016/j.biocel.2008.04.025
↑ ^22.0 ^22.1 ^22.2 ^22.3 ^22.4 Nelson, D., and Cox, M. Lehninger Principles of Biochemistry. 2008. 5th edition. W. H. Freeman and Company, New York, New York, USA. pp. 462-465.
↑ Hurley JB, Spencer M, Niemi GA. Rhodopsin phosphorylation and its role in photoreceptor function. Vision Res. 1998 May;38(10):1341-52. PMID:9667002
↑ ^24.0 ^24.1 ^24.2 Park JH, Scheerer P, Hofmann KP, Choe HW, Ernst OP. Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature. 2008 Jul 10;454(7201):183-7. Epub 2008 Jun 18. PMID:18563085 doi:10.1038/nature07063
↑ ^25.0 ^25.1 Surya A, Knox BE. Enhancement of opsin activity by all-trans-retinal. Exp Eye Res. 1998 May;66(5):599-603. PMID:9628807 doi:10.1006/exer.1997.0453

References

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Cinting Lim, Michal Harel, Wayne Decatur, Alexander Berchansky, Joel L. Sussman, Jaime Prilusky

[Article1-1] Hornak V, Ahuja S, Eilers M, Goncalves JA, Sheves M, Reeves PJ, Smith SO. Light activation of rhodopsin: insights from molecular dynamics simulations guided by solid-state NMR distance restraints. J Mol Biol. 2010 Feb 26;396(3):510-27. Epub 2009 Dec 11. PMID:20004206 doi:10.1016/j.jmb.2009.12.003

[Article12-2] 2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 Sakmar TP. Structure of rhodopsin and the superfamily of seven-helical receptors: the same and not the same. Curr Opin Cell Biol. 2002 Apr;14(2):189-95. PMID:11891118

[3] Tsunoda SP, Prigge M, Abe-Yoshizumi R, Inoue K, Kozaki Y, Ishizuka T, Yawo H, Yizhar O, Kandori H. Functional characterization of sodium-pumping rhodopsins with different pumping properties. PLoS One. 2017 Jul 27;12(7):e0179232. PMID:28749956 doi:10.1371/journal.pone.0179232

[4] Yun JH, Li X, Yue J, Park JH, Jin Z, Li C, Hu H, Shi Y, Pandey S, Carbajo S, Boutet S, Hunter MS, Liang M, Sierra RG, Lane TJ, Zhou L, Weierstall U, Zatsepin NA, Ohki M, Tame JRH, Park SY, Spence JCH, Zhang W, Schmidt M, Lee W, Liu H. Early-stage dynamics of chloride ion-pumping rhodopsin revealed by a femtosecond X-ray laser. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13). pii: 2020486118. doi:, 10.1073/pnas.2020486118. PMID:33753488 doi:https://dx.doi.org/10.1073/pnas.2020486118

[5] Choe HW, Kim YJ, Park JH, Morizumi T, Pai EF, Krauss N, Hofmann KP, Scheerer P, Ernst OP. Crystal structure of metarhodopsin II. Nature. 2011 Mar 9. PMID:21389988 doi:10.1038/nature09789

[6] Schapiro I, Ryazantsev MN, Frutos LM, Ferré N, Lindh R, Olivucci M. The ultrafast photoisomerizations of rhodopsin and bathorhodopsin are modulated by bond length alternation and HOOP driven electronic effects. J Am Chem Soc. 2011 Mar 16;133(10):3354-64. PMID:21341699 doi:10.1021/ja1056196

[7] Pan D, Mathies RA. Chromophore structure in lumirhodopsin and metarhodopsin I by time-resolved resonance Raman microchip spectroscopy. Biochemistry. 2001 Jul 3;40(26):7929-36. PMID:11425321 doi:10.1021/bi010670x

[8] Zhao S, Cunha C, Zhang F, Liu Q, Gloss B, Deisseroth K, Augustine GJ, Feng G. Improved expression of halorhodopsin for light-induced silencing of neuronal activity. Brain Cell Biol. 2008 Aug;36(1-4):141-54. PMID:18931914 doi:10.1007/s11068-008-9034-7

[9] Ganapathy S, Kratz S, Chen Q, Hellingwerf KJ, de Groot HJM, Rothschild KJ, de Grip WJ. Redshifted and Near-infrared Active Analog Pigments Based upon Archaerhodopsin-3. Photochem Photobiol. 2019 Jul;95(4):959-968. PMID:30860604 doi:10.1111/php.13093

[10] Bamann C, Bamberg E, Wachtveitl J, Glaubitz C. Proteorhodopsin. Biochim Biophys Acta. 2014 May;1837(5):614-25. doi: 10.1016/j.bbabio.2013.09.010., Epub 2013 Sep 20. PMID:24060527 doi:https://dx.doi.org/10.1016/j.bbabio.2013.09.010

[11] Balashov SP, Lanyi JK. Xanthorhodopsin: Proton pump with a carotenoid antenna. Cell Mol Life Sci. 2007 Sep;64(18):2323-8. PMID:17571211 doi:10.1007/s00018-007-7167-y

[Article20-12] 12.0 ^12.1 ^12.2 ^12.3 Kristiansen K. Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function. Pharmacol Ther. 2004 Jul;103(1):21-80. PMID:15251227 doi:10.1016/j.pharmthera.2004.05.002

[RecentOthers-13] Millar RP, Newton CL. The year in G protein-coupled receptor research. Mol Endocrinol. 2010 Jan;24(1):261-74. Epub 2009 Dec 17. PMID:20019124 doi:10.1210/me.2009-0473

[Article10-14] 14.0 ^14.1 ^14.2 Meng EC, Bourne HR. Receptor activation: what does the rhodopsin structure tell us? Trends Pharmacol Sci. 2001 Nov;22(11):587-93. PMID:11698103

[Article4-15] 15.0 ^15.1 Shieh T, Han M, Sakmar TP, Smith SO. The steric trigger in rhodopsin activation. J Mol Biol. 1997 Jun 13;269(3):373-84. PMID:9199406 doi:10.1006/jmbi.1997.1035

[Article9-16] 16.0 ^16.1 ^16.2 ^16.3 ^16.4 ^16.5 ^16.6 ^16.7 ^16.8 Okada T, Ernst OP, Palczewski K, Hofmann KP. Activation of rhodopsin: new insights from structural and biochemical studies. Trends Biochem Sci. 2001 May;26(5):318-24. PMID:11343925

[ReferenceArticle-17] 17.0 ^17.1 Okada T, Sugihara M, Bondar AN, Elstner M, Entel P, Buss V. The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure. J Mol Biol. 2004 Sep 10;342(2):571-83. PMID:15327956 doi:10.1016/j.jmb.2004.07.044

[Article3-18] 18.0 ^18.1 Janz JM, Farrens DL. Assessing structural elements that influence Schiff base stability: mutants E113Q and D190N destabilize rhodopsin through different mechanisms. Vision Res. 2003 Dec;43(28):2991-3002. PMID:14611935

[Article19-19] 19.0 ^19.1 ^19.2 Kisselev OG. Focus on molecules: rhodopsin. Exp Eye Res. 2005 Oct;81(4):366-7. PMID:16051215 doi:10.1016/j.exer.2005.06.018

[Article2-20] 20.0 ^20.1 ^20.2 Verhoeven MA, Bovee-Geurts PH, de Groot HJ, Lugtenburg J, DeGrip WJ. Methyl substituents at the 11 or 12 position of retinal profoundly and differentially affect photochemistry and signalling activity of rhodopsin. J Mol Biol. 2006 Oct 13;363(1):98-113. Epub 2006 Jul 28. PMID:16962138 doi:10.1016/j.jmb.2006.07.039

[Article6-21] 21.0 ^21.1 ^21.2 ^21.3 Morris MB, Dastmalchi S, Church WB. Rhodopsin: structure, signal transduction and oligomerisation. Int J Biochem Cell Biol. 2009 Apr;41(4):721-4. Epub 2008 Aug 3. PMID:18692154 doi:10.1016/j.biocel.2008.04.025

[Textbook-22] 22.0 ^22.1 ^22.2 ^22.3 ^22.4 Nelson, D., and Cox, M. Lehninger Principles of Biochemistry. 2008. 5th edition. W. H. Freeman and Company, New York, New York, USA. pp. 462-465.

[Article7-23] Hurley JB, Spencer M, Niemi GA. Rhodopsin phosphorylation and its role in photoreceptor function. Vision Res. 1998 May;38(10):1341-52. PMID:9667002

[ArticleOpsin2-24] 24.0 ^24.1 ^24.2 Park JH, Scheerer P, Hofmann KP, Choe HW, Ernst OP. Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature. 2008 Jul 10;454(7201):183-7. Epub 2008 Jun 18. PMID:18563085 doi:10.1038/nature07063

[ArticleOpsin1-25] 25.0 ^25.1 Surya A, Knox BE. Enhancement of opsin activity by all-trans-retinal. Exp Eye Res. 1998 May;66(5):599-603. PMID:9628807 doi:10.1006/exer.1997.0453

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@@ Line 11: / Line 11: @@
 *'''Archaerhodopsin''' is a light-driven proton pump<ref>PMID:30860604</ref>.
 *'''Proteorhodopsin''' is the most abundant proton pump<ref>PMID:24060527</ref>.
+*'''Xanthorhodopsin''' contains a cartenoid/retinal complex in which the carotenoid serves as light-harvesting antennais<ref>PMID:17571211</ref>.
 See also [[Transmembrane (cell surface) receptors]]