Melanopsin

Source: Wikipedia, the free encyclopedia.

OPN4
Identifiers
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Melanopsin is a type of

photopsin (types I, II, and III) in the rod and cone
photoreceptor cells, respectively.

In humans, melanopsin is found in

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 the suprachiasmatic nucleus (SCN), also known as the central "body clock", in mammals.[9] Melanopsin plays an important non-image-forming role in the setting of circadian rhythms as well as other functions. Mutations in the Opn4 gene can lead to clinical disorders, such as Seasonal 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

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

Melanopsin was discovered by

orthologs in 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 named

intrinsically photosensitive Retinal Ganglion Cells (ipRGCs).[17] They constitute a third class of photoreceptor cells in the mammalian retina, besides the already known rods and cones, and were shown to be the principal conduit for light input to circadian photoentrainment.[16] In fact, it was later demonstrated by Satchidananda Panda and colleagues that melanopsin pigment may be involved in entrainment of a circadian oscillator to light cycles in mammals since melanopsin was necessary for blind mice to respond to light.[18]

Species distribution

Mammals have

orthologous melanopsin genes named Opn4m, which are derived from one branch of the Opn4 family, 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 from Opn4m about 360 million years ago.[20] Mammals lost the gene Opn4x relatively 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

The human melanopsin gene, opn4, is expressed in

Paralogs of Opn4 include OPN1LW, OPN1MW, rhodopsin and encephalopsin.[21]

Melanopsin, like all other animal

Schiff-base,[23][24] which makes melanopsin light sensitive. In fact this is abolished if the lysine is replaced by an alanine.[25]

Melanopsin is more closely related to

photoisomerase activity.[31]

Function

retinal ganglion cells
, a small percentage of which contain melanopsin. Light strikes the ganglia first, the rods and cones last.

Melanopsin-containing ganglion cells,

ipRGCs contribute 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,

photoisomerase regeneration 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 the visible 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

When light with an appropriate frequency enters the eye, it activates the melanopsin contained in

olivary 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 of melatonin release from the pineal gland.[38][39] The ipRGCs in the mammalian retina are one terminus of the retinohypothalamic tract that projects to the suprachiasmatic nucleus (SCN) of the hypothalamus. The suprachiasmatic nucleus is sometimes described as the brain's "master clock",[40] as it maintains the circadian 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 the

pituitary 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

Melanopsin serves an important role in the photoentrainment of circadian rhythms in mammals. An organism that is photoentrained has aligned its activity to an approximately 24-hour cycle, the solar cycle on Earth.[43] In mammals, melanopsin expressing axons target the suprachiasmatic nucleus (SCN) through the retinohypothalamic 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 their melatonin concentrations. 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 practice enucleation of 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 that

circadian clock.[15]

Melanopsin-

photopsin and 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

Melanopsin undergoes

carboxy tail as a way to deactivate its function. Compared to other opsins, melanopsin has an unusually long carboxy tail that contains 37 serine and threonine amino 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,

mRNA in ipRGCs.[50]

Clinical significance

The discovery of the role of melanopsin in non-image forming vision has led to a growth in

Seasonal 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 to migraine pain.[52]

Restoration of vision

There has been recent research on the role of melanopsin in optogenetic therapy for patients with the degenerative eye disease retinitis pigmentosa (RP).[53] Reintroducing functional melanopsin into the eyes of mice with retinal degeneration restores the pupillary 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

Melanopsin may aid in controlling sleep cycles and wakefulness. Tsunematsu and colleagues created

optical fibers), the transgenic mice could successfully transition from slow-wave sleep (SWS), which is commonly known as "deep sleep," to long-lasting wakefulness. After switching off the blue light, the hypothalamic orexin neurons 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

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 produce

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 reduced hyperglycemia, 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

References

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Further reading

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