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Melanopsin

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OPN4
Identifiers
AliasesOPN4,MOP, opsin 4
External IDsOMIM:606665;MGI:1353425;HomoloGene:69152;GeneCards:OPN4;OMA:OPN4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

94233

30044

Ensembl

ENSG00000122375

ENSMUSG00000021799

UniProt

Q9UHM6

Q9QXZ9

RefSeq (mRNA)

NM_033282
NM_001030015

NM_001128599
NM_013887

RefSeq (protein)

NP_001025186
NP_150598

NP_001122071
NP_038915

Location (UCSC)Chr 10: 86.65 – 86.67 MbChr 14: 34.31 – 34.32 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Melanopsinis a type ofphotopigmentbelonging to a larger family of light-sensitiveretinal proteinscalledopsinsand encoded by the geneOpn4.[5]In the mammalianretina,there are two additional categories of opsins, both involved in the formation of visual images:rhodopsinandphotopsin(types I, II, and III) in therodandconephotoreceptor cells, respectively.

In humans, melanopsin is found inintrinsically photosensitive retinal ganglion cells(ipRGCs).[6]It is also found in the iris of mice and primates.[7]Melanopsin is also found in rats,amphioxus,and other chordates.[8]ipRGCs are photoreceptor cells which are particularly sensitive to the absorption of short-wavelength (blue) visible light and communicate information directly to the area of the brain called thesuprachiasmatic nucleus(SCN), also known as the central "body clock", in mammals.[9]Melanopsin plays an important non-image-forming role in thesettingof circadian rhythms as well as other functions. Mutations in theOpn4gene can lead to clinical disorders, such asSeasonal Affective Disorder(SAD).[10]According to one study, melanopsin has been found in eighteen sites in the human brain (outside the retinohypothalamic tract), intracellularly, in a granular pattern, in the cerebral cortex, the cerebellar cortex and several phylogenetically old regions, primarily in neuronal soma, not in nuclei.[11]Melanopsin is also expressed in human cones. However, only 0.11% to 0.55% of human cones express melanopsin and are exclusively found in the peripheral regions of the retina.[12]The human peripheral retina senses light at high intensities that is best explained by four different photopigment classes.[13]

Discovery[edit]

Nerve cells containing melanopsin are shown in blue in the spread out retina.

Melanopsin was discovered byIgnacio Provencioas a newopsinin themelanophores,or light-sensitive skin cells, of theAfrican clawed frogin 1998.[14]A year later, researchers found that mice without anyrodsorcones,the cells involved in image-forming vision, stillentrainedto a light-dark cycle.[15]This observation led to the conclusion that neither rods nor cones, located in the outerretina,are necessary for circadian entrainment and that a third class of photoreceptor exists in the mammalian eye.[5]Provencio and colleagues then found in 2000 that melanopsin is also present in mouse retina, specifically inganglion cells,and that it mediates non-visual photoreceptive tasks.[16]Melanopsin is encoded by theOpn4gene withorthologsin a variety of organisms.[5]

These retinal ganglion cells were found to be innately photosensitive, since they responded to light even while isolated, and were thus namedintrinsically photosensitive Retinal Ganglion Cells (ipRGCs).[17]They constitute a third class ofphotoreceptor cellsin the mammalian retina, besides the already known rods and cones, and were shown to be the principal conduit for light input to circadianphotoentrainment.[16]In fact, it was later demonstrated by Satchidananda Panda and colleagues that melanopsin pigment may be involved in entrainment of acircadian oscillatorto light cycles in mammals since melanopsin was necessary for blind mice to respond to light.[18]

Species distribution[edit]

Mammals haveorthologousmelanopsin genes namedOpn4m,which are derived from one branch of theOpn4family, and are approximately 50-55% conserved.[19]However, non-mammalian vertebrates, including chickens and zebrafish, have another version of the melanopsin gene,Opn4x,which appears to have a distinct lineage that diverged fromOpn4mabout 360 million years ago.[20]Mammals lost the geneOpn4xrelatively early in their evolution, leading to a general reduction in photosensory capability. It is thought that this event can be explained by the fact that this occurred during the time in which nocturnal mammals were evolving.[19]

Structure[edit]

The human melanopsin gene,opn4,is expressed inipRGCs,which comprises only 1-2% ofRGCsin the inner mammalian retina, as studied bySamer Hattarand colleagues.[9]The gene spans approximately 11.8 kb and is mapped to the long arm ofchromosome 10.The gene includes nineintronsand tenexonscompared to the four to seven exons typically found in other human opsins.[16]In non-mammalian vertebrates, melanopsin is found in a wider subset of retinal cells, as well as in photosensitive structures outside the retina, such as theirismuscle of the eye, deep brain regions, thepineal gland,and the skin.[19]ParalogsofOpn4includeOPN1LW,OPN1MW,rhodopsinandencephalopsin.[21]

Melanopsin, like all other animalopsins(e.g.rhodopsin), is aG-protein-coupled receptor (GPCR).The melanopsin protein has an extarcellularN-terminal domain,an intracellularC-terminal domain,and sevenalpha helicesspanning through the plasma membrane.[14]The seventh helix has alysinethat corresponds to Lys2967.43incattlerhodopsin[14]and that is conserved in almost all opsins.[22]This lysine binds covalentlyretinalvia aSchiff-base,[23][24]which makes melanopsin light sensitive. In fact this is abolished if the lysine is replaced by analanine.[25]

Melanopsin is more closely related toinvertebratevisual opsins, which are rhabdomeric opsin, than tovertebratevisual opsins, which are cliary opsins.[14][26][27]This is also reflected by the downstreamsignaling cascade,melanopsin couples in ipRGCs to theG-proteinsG(q),G(11),andG(14),which are all of the G(q)-type.[28]In fact, they can functionally replace each other, as aknocking outonly two of them has nophenotypicaleffect.[29]The G-proteins activate thephospholipase CPLCB4,[7]which causes theTRP-channelsTRPC6andTRPC7mediate to open so that the celldepolarizes.[17][7]This is like in the photoreceptor cells of theDrosophilaeye, and in contrast to the vertebraterodandconecells, wherephototransductioneventually makes the cellshyperpolarize.[30]Like other rhabdomeric opsins, Melanopsin has intrinsicphotoisomeraseactivity.[31]

Function[edit]

Diagram showing a cross-section of the retina. The area near the top, labeled "Ganglionic layer", containsretinal ganglion cells,a small percentage of which contain melanopsin. Light strikes the ganglia first, the rods and cones last.

Melanopsin-containing ganglion cells,[32]like rods and cones, exhibit both light and darkadaptation;they adjust their sensitivity according to the recent history of light exposure.[33]However, while rods and cones are responsible for the reception of images, patterns, motion, and color, melanopsin-containingipRGCscontribute to various reflexive responses of the brain and body to the presence of light.[17]

Evidence for melanopsin's physiological light detection has been tested in mice. A mouse cell line that is not normally photosensitive,Neuro-2a,is rendered light-sensitive by the addition of human melanopsin. The photoresponse is selectively sensitive to short-wavelength light (peak absorption ~479 nm),[34][35]and has an intrinsicphotoisomeraseregeneration function that is chromatically shifted to longer wavelengths.[36]

Melanopsin photoreceptors are sensitive to a range of wavelengths and reach peak light absorption at blue light wavelengths around 480 nanometers.[37]Other wavelengths of light activate the melanopsin signaling system with decreasing efficiency as they move away from the optimum 480 nm. For example, shorter wavelengths around 445 nm (closer to violet in thevisible spectrum) are half as effective for melanopsin photoreceptor stimulation as light at 480 nm.[37]

Melanopsin in the iris of some, primarily nocturnal, mammals closes the iris when it is exposed to light. This local pupil light reflex (PLR) is absent from primates, even though their irises express melanopsin.[7]

Mechanism[edit]

When light with an appropriate frequency enters the eye, it activates the melanopsin contained inintrinsically photosensitive retinal ganglion cells(ipRGCs), triggering anaction potential.These neuronal electrical signals travel through neuronalaxonsto specific brain targets, such as the center of pupillary control called theolivary pretectal nucleus(OPN) of the midbrain. Consequently, stimulation of melanopsin in ipRGCs mediates behavioral and physiological responses to light, such as pupil constriction and inhibition ofmelatoninrelease from thepineal gland.[38][39]The ipRGCs in the mammalian retina are one terminus of theretinohypothalamic tractthat projects to thesuprachiasmatic nucleus(SCN) of thehypothalamus.The suprachiasmatic nucleus is sometimes described as the brain's "master clock",[40]as it maintains thecircadian rhythm,and nerve signals from ipRGCs to the SCN entrain the internal circadian rhythm to the rising and setting of the sun.[9]The SCN also receives input from rods and cones through the retinohypothalamic tract, so information from all three photosensitive cell types (rods, cones, and ipRGCs) in the mammalian retina are transmitted to the (SCN) SCN.[41]

Melanopsin-containing ganglion cells are thought to influence these targets by releasing theneurotransmittersglutamateandpituitary adenylate cyclase activating polypeptide(PACAP) from their axon terminals.[42]Melanopsin-containing ganglion cells also receive input from rods and cones that can add to the input to these pathways.

Effects on circadian rhythm[edit]

Melanopsin serves an important role in thephotoentrainmentof circadian rhythms in mammals. An organism that isphotoentrainedhas aligned its activity to an approximately 24-hour cycle, thesolar cycleon Earth.[43]In mammals, melanopsin expressing axons target thesuprachiasmatic nucleus (SCN)through theretinohypothalamic tract(RHT).[9]

In mammals, the eye is the main photosensitive organ for the transmission of light signals to the brain. However, blind humans are still able to entrain to the environmental light-dark cycle, despite having no conscious perception of the light. One study exposed subjects to bright light for a prolonged duration of time and measured theirmelatoninconcentrations. Melatonin was not only suppressed in visually unimpaired humans, but also in blind participants, suggesting that the photic pathway used by the circadian system is functionally intact despite blindness.[44]Therefore, physicians no longer practiceenucleationof blind patients, or removal of the eyes at birth, since the eyes play a critical role in the photoentrainment of the circadian pacemaker.

In mutant breeds of mice that lacked only rods, only cones, or both rods and cones, all breeds of mice still entrained to changing light stimuli in the environment, but with a limited response, suggesting thatrodsandconesare not necessary for circadian photoentrainment and that the mammalian eye must have another photopigment required for the regulation of thecircadianclock.[15]

Melanopsin-knockout micedisplay reduced photoentrainment. In comparison to wild-type mice that expressed melanopsin normally, deficits in light-induced phase shifts in locomotion activity were noted in melanopsin-null mice (Opn4 -/-).[18]These melanopsin-deficient mice did not completely lose their circadian rhythms, as they were still able to entrain to changing environmental stimuli, albeit more slowly than normal.[45]This indicated that, although melanopsin is sufficient for entrainment, it must work in conjunction with other photopigments for normal photoentrainment activity. Triple-mutant mice that were rod-less, cone-less, and melanopsin-less display a complete loss in the circadian rhythms, so all three photopigments in these photoreceptors,rhodopsin,photopsinand melanopsin, are necessary for photoentrainment.[46]Therefore, there is a functional redundancy between the three photopigments in the photoentrainment pathway of mammals. Deletion of only one photopigment does not eliminate the organism's ability to entrain to environmental light-dark cycles, but it does reduce the intensity of the response.

Regulation[edit]

Melanopsin undergoesphosphorylationon its intracellularcarboxy tailas a way to deactivate its function. Compared to other opsins, melanopsin has an unusually long carboxy tail that contains 37serineandthreonineamino acid sites that could undergo phosphorylation.[47]However, a cluster of seven amino acids are sufficient to deactivate zebrafish melanopsin. These sites are dephosphorylated when melanopsin is exposed to light and are unique from those that regulate rhodopsin.[48]They are important for proper response to calcium ions in ipRGCs; lack of functional phosphorylation sites, particularly at serine-381 and serine-398, reduce the cell's response to light-induced calcium ion influx when voltage-gated calcium ion channels open.[49]

In terms of the gene Opn4,Dopamine(DA) is a factor in the regulation of melanopsinmRNAin ipRGCs.[50]

Clinical significance[edit]

The discovery of the role of melanopsin in non-image forming vision has led to a growth inoptogenetics.This field has shown promise in clinical applications, including the treatment of human eye diseases such asretinitis pigmentosaanddiabetes.[51]Amissense mutationin Opn4, P10L, has been implicated in 5% of patients withSeasonal Affective Disorder(SAD).[10]This is a condition in which people experience depressive thoughts in the winter due to decreased available light. Additionally, a melanopsin based receptor has been linked tomigrainepain.[52]

Restoration of vision[edit]

There has been recent research on the role of melanopsin inoptogenetictherapy for patients with the degenerative eye diseaseretinitis pigmentosa(RP).[53]Reintroducing functional melanopsin into the eyes of mice with retinal degeneration restores thepupillary light reflex (PLR).These same mice could also distinguish light stimuli from dark stimuli and showed increased sensitivity to room light. The higher sensitivity demonstrated by these mice shows promise for vision restoration that may be applicable to humans and human eye diseases.[51][54]

Control of sleep/wake patterns[edit]

Melanopsin may aid in controlling sleep cycles and wakefulness. Tsunematsu and colleagues createdtransgenicmice that expressed melanopsin inhypothalamicorexinneurons. With a short 4-second pulse of blue light (guided byoptical fibers), the transgenic mice could successfully transition fromslow-wave sleep(SWS), which is commonly known as "deep sleep," to long-lasting wakefulness. After switching off the blue light, the hypothalamicorexinneurons showed activity for several tens of seconds.[51][55]It has been shown that rods and cones play no role in the onset of sleep by light, distinguishing them from ipRGCs and melanopsin. This provides strong evidence that there is a link between ipRGCs in humans and alertness, particularly with high frequency light (e.g. blue light). Therefore, melanopsin can be used as a therapeutic target for controlling the sleep-wake cycle.[56]

Regulation of blood glucose levels[edit]

In a paper published by Ye and colleagues in 2011, melanopsin was utilized to create an optogenetic synthetic transcription device that was tested in a therapeutic setting to produceFc-glucagon-like peptide 1(Fc-GLP-1), a fusion protein that helps control blood glucose levels in mammals withType II Diabetes.The researchers subcutaneously implanted mice with microencapsulated transgenicHEK 293 cellsthat were cotransfected with two vectors including the melanopsin gene and the gene of interest under an NFAT (nuclear factor of activated T cells) promoter, respectively. It is through this engineered pathway that they successfully controlled the expression of Fc-GLP-1 in doubly recessive diabetic mice and reducedhyperglycemia,or high blood glucose levels, in these mice. This shows promise for the use of melanopsin as an optogenetic tool for the treatment of Type II diabetes.[51][57]

See also[edit]

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Further reading[edit]

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