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Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. Two other opsins in the mammalian retina are both involved in the formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.
Melanopsin is found in intrinsically photosensitive retinal ganglion cells (iPRGCs) in mammalian vertebrates. In non-mammalian vertebrates, however, melanopsin is found in the retina as well as in other tissues, including but not limited to the brain, the pineal gland, and the skin. iPRGCs are photoreceptor cells which are particularly sensitive to the absorption of short-wavelength visible light and communicate information directly to the area of the brain called the suprachiasmatic nucleus (SCN), otherwise known as the central “body clock” in mammals. Consequently, 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).
Melanopsin was first discovered by Ignacio Provencio as a novel opsin in the melanophores, or light sensitive skin cells, of the African clawed frog in 1998. A year later, researchers found that mice without any rods or cones still entrained to a light-dark cycle. This observation led to the conclusion that neither rods nor cones, located in the outer retina, are necessary for circadian entrainment and that a third class of photoreceptor exists in the mammalian eye. Provencio and colleagues then found in 2000 that melanopsin is also present in mouse retina, specifically in ganglion cells, and that it mediates non visual photoreceptive tasks. Melanopsin was found to be encoded by Opn4 with orthologs in a variety of organisms.
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). 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. 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.
The human melanopsin gene, opn4, is only expressed in 1-2% of ipRGCs in the inner mammalian retina, as studied by Samer Hattar and colleagues. The gene spans approximately 11.8 kb and is mapped to the long arm of chromosome 10 (10q22). The gene includes nine introns and ten exons compared to the four to seven exons typically found in other human opsins. 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 the iris muscle of the eye, deep brain regions, the pineal gland, and the skin. Paralogs of Opn4 include OPN1LW, OPN1MW, RHO and OPN3 and were discovered by the Genome Project.
Melanopsin, like all other opsins (e.g. rhodopsin), is a member of the G-protein coupled receptor (GPCR) family. The melanopsin protein has seven alpha helices integrated in the plasma membrane, an N-terminal domain and a C-terminal domain. It resembles invertebrate opsins far more than vertebrate photopigments, especially in its amino acid sequence and downstream signaling cascade. Like invertebrate opsins, it appears to be a photopigment with intrinsic photoisomerase activity and signals through a G-protein of the Gq family.
Mammals have orthologous melanopsin genes named Opn4m, which are derived from one branch of the Opn4 family, and are approximately 50-55% conserved. 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. 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.
Melanopsin-containing ganglion cells, like rods and cones, exhibit both light and dark adaptation; they adjust their sensitivity according to the recent history of light exposure. However, while rods and cones are responsible for the analysis of images, patterns, motion, and color, melanopsin-containing ipRGCs contribute to various reflexive responses of the brain and body to the presence of light.
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), and has an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths.
Melanopsin photoreceptors are sensitive to a range of wavelengths and reach peak light absorption at blue light wavelengths around 488 nanometers. Other wavelengths of light activate the melanopsin signaling system with decreasing efficiency as they move away from the optimum 488 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 488 nm.
When light enters the eye, ipRGCs discharge nerve impulses. These neuronal electrical signals travel through neuronal axons to specific brain targets, such as the center of pupillary control called the olivary pretectal nucleus (OPN) of the midbrain. Consequently, stimulation of melanopsin contributes to the regulation of behavioral responses to light, such as pupil size and melatonin release from the pineal gland. The ipRGCs in the mammalian retina form the retinohypothalamic tract that projects to the suprachiasmatic nucleus (SCN), a region of the brain in the hypothalamus which is considered the master pacemaker of circadian rhythms. The retinohypothalamic tract also receives input from rods and cones. Thus, information from all three opsins in the mammalian retina integrate before transmission to the SCN.
Melanopsin-containing ganglion cells are thought to influence these targets by releasing the neurotransmitters glutamate and pituitary adenylate cyclase activating polypeptide (PACAP) from their axon terminals. 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. In mammals, melanopsin expressing axons target the suprachiasmatic nucleus (SCN) through the retinohypothalamic tract (RHT).
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. 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 rods and cones are not necessary for circadian photoentrainment and that the mammalian eye must have another photopigment required for the regulation of the circadian clock.
Melanopsin-knockout mice display 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 -/-). 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. 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, photopsin and melanopsin, are necessary for photoentrainment. 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.
Melanopsin undergoes phosphorylation on its intracellular 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. 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. 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.
The discovery of the role of melanopsin in non-image forming vision has led to a growth in optogenetics. This field has shown promise in clinical applications, including the treatment of human eye diseases such as retinitis pigmentosa and diabetes. A missense mutation in Opn4, P10L, has been implicated in 5% of patients with Seasonal Affective Disorder (SAD). 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 migraine pain.
There has been recent research on the role of melanopsin in optogenetic therapy for patients with the degenerative eye disease retinitis pigmentosa (RP). 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.
Controlling sleep/wake patterns
Melanopsin may aid in controlling sleep cycles and wakefulness. Tsunematsu and colleagues created transgenic mice that expressed melanopsin in hypothalamic orexin neurons. With a short 4-second pulse of blue light (guided by 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. 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.
Regulating blood glucose levels
Melanopsin plays a role in blood glucose levels, and therefore Type II Diabetes. Ye and colleagues created transgenic mice, expressing melanopsin in the under-skin of the intraperitoneal (abdominal) region and showed that melanopsin can be used to control intracellular calcium ion influx/efflux by regulating the transcription factor of nuclear factor of activated T cells (NFAT) family in mice. The NFAT signaling pathway utilizes calmodulin, a calcium ion-sensitive protein, to increase intracellular calcium ions. It is through this pathway that they successfully controlled the expression of glucagon-like peptide 1 in the melanopsin-transgenic mice and reduced hyperglycemia, or high blood glucose levels, in type II diabetic mice. This shows promise for melanopsin and optogenetics as a treatment for type II diabetes.
- Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs)
- Suprachiasmatic nucleus (SCN)
- Retinohypothalamic tract
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