Melanopsin is a photopigment found in specialized photosensitive ganglion cells of the retina that are involved in the regulation of circadian rhythms, pupillary light reflex, and other non-visual responses to light. In structure, melanopsin is an opsin, a retinylidene protein variety of G-protein-coupled receptor. Melanopsin is most sensitive to blue light. A melanopsin based receptor has been linked to the association between light sensitivity and migraine pain.
Melanopsin differs from other opsin photopigments in vertebrates. In fact, it resembles invertebrate opsins in many respects, including its amino acid sequence and downstream signaling cascade. Like invertebrate opsins, melanopsin appears to be a bistable photopigment, with intrinsic photoisomerase activity, and to signal through a G-protein of the Gq family.
Takashi Yoshimura and Shizufumi Ebihara of Nagoya University in Japan discovered in 1994 that although the phase response curves of retinally degenerate CBA/J mice showed smaller delays in the early subjective night than normal CBA/N mice, CBA/J mice could show normal magnitude phase shifts if exposed to sufficiently high intensities of light. From this, they concluded that differences in the shapes of PRCs were due to the differences in photosensitivity of the two mouse strains, and that reduced circadian photosensitivity may be caused by retinal degeneration.
Melanopsin was originally discovered by Ignacio Provencio and his colleagues in 1998, in the specialized light sensitive cells of frog skin. In 1999, Russell G. Foster showed that entrainment of mice to a light-dark cycle was maintained in the absence of rods and cones. Such an observation led him 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. In 2000, Provencio determined that melanopsin was expressed only in the inner retina of mammals, including humans, and that it mediated nonvisual photoreceptive tasks.
The first recordings of light responses from melanopsin-containing ganglion cells were obtained by David Berson and colleagues at Brown University. They also showed that these responses persisted when pharmacological agents blocked synaptic communication in the retina, and when single melanopsin-containing ganglion cells were physically isolated from other retinal cells. These findings showed that melanopsin-containing ganglion cells are intrinsically photosensitive, and they were thus named intrinsically photosensitive Retinal Ganglion Cells (ipRGCs). They constitute a third class of photoreceptor cells in the mammalian retina, beside the already known rod and cone photoreceptors.
Evidence supporting prior theories that melanopsin is the photopigment responsible for the entrainment of the central "body clock", the suprachiasmatic nuclei (SCN), in mammals was provided by King-Wai Yau and colleagues at Princeton. Fluorescent immunocytochemistry was used to visualize melanopsin distribution throughout the rat retina and showed that melanopsin was found in approximately 2.5% of the total rat retinal ganglion cells (RGCs) and that these cells were indeed ipRGCs. Using β-galactosidase as a marker for the melanopsin gene, X-gal labeling of these ipRGCs showed that their axons directly target the SCN, providing further evidence that melanopsin is important in entrainment through the retinohypothalamic tract (RHT).
Melanopsin-containing ganglion cells exhibit both light and dark adaptation, that is, that they adjust their sensitivity according to the recent history of light exposure. In this respect, they are similar to rods and cones. Whereas rods and cones are responsible for the analysis of images, patterns, motion and color, a number of studies have shown that melanopsin-containing ganglion cells contribute to various reflexive responses of the brain and body to the presence of (day)light.
A mouse paraneuronal cell line (Neuro-2a), which normally is not photosensitive, is rendered photoreceptive by the addition of human melanopsin. Under such conditions, melanopsin acts as a sensory photopigment, performing physiological light detection. The melanopsin photoresponse is selectively sensitive to short-wavelength light (peak absorption ~480 nm), while it also has an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths.
Melanopsin photoreceptors are sensitive to a range of light wavelengths. Melanopsin photoreceptors 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 get shorter or longer than 488 nm. For example, shorter wavelengths around 445 nm (closer to violet in the visible spectrum) are half as efficient at melanopsin photoreceptor stimulation as light at 488 nm. Longer wavelengths around 529 nm (in the bluish-green part of the visible spectrum) are also half as efficient as light at 488 nm.
Dopamine (DA) is a factor in the regulation of melanopsin mRNA in ipRGCs. Because DA synthesis and release in the rat retina are under the control of rods and cones, it appears that rods and cones, in conjunction with or possibly with the exclusion of direct circadian or photic input, control transcription of melanopsin.
When light activates the melanopsin signaling system, the melanopsin-containing ganglion cells discharge nerve impulses, which are conducted through their axons to specific brain targets. These targets include the olivary pretectal nucleus (OPN) (a center responsible for controlling the pupil of the eye) and, through the retinohypothalamic tract, the suprachiasmatic nucleus of the hypothalamus (the master pacemaker of circadian rhythms). Melanopsin-containing ganglion cells are thought to influence these targets by releasing from their axon terminals the neurotransmitters glutamate and pituitary adenylate cyclase activating polypeptide (PACAP). Melanopsin-containing ganglion cells also receive input from rods and cones that modifies or adds to the input to these pathways.
Effects on light entrainment
Experiments have shown that entrainment to light, by which periods of behavioral activity or inactivity (sleep) are synchronized with the light-dark cycle, is not as effective in melanopsin knockout mice. Entrainment is lost entirely when melanopsin-expressing cells are killed, as these cells are also required for transmission of rod-cone light information. Mice lacking rods and cones still exhibit circadian entrainment, but also show reduced response to light. Such mice can, however, distinguish between visual patterns. The pupillary reflex is also retained in mice lacking rods and cones but has reduced sensitivity, identifying a crucial input from the rods and cones. Without melanopsin, rods, and cones, mice fail to entrain to circadian rhythms and the pupillary reflex is lost.
ipRGCs are responsible for the ability of some blind people to entrain to the 24-hour light/dark cycles despite loss of image-forming vision. These people have intact retinohypothalamic tracts that allow signaling from the ipRGCs to the suprachiasmatic nucleus. Moreover, ipRGCs have a role in conventional vision; ipRGCs allow mice without rods or cones to show non-circadian light responses and to encode illumination in the visual cortex over a million-fold range.
Melanopsin genes have been described in all vertebrate classes, and an extra melanopsin ortholog has been discovered in fish, bird, and amphibian genomes. Within the mammals studied thus far (which includes rodents, primates, and humans), the melanopsin protein has a similar pattern of tissue distribution; the protein is expressed only in the retina, and only in 1-2% of retinal ganglion cells. 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.
Mammals have orthologous melanopsin genes named Opn4m, which are derived from one branch of the Opn4 family. However, non-mammalian vertebrates have two versions of the melanopsin gene, Opn4m and Opn4x. Chicken Opn4m appears capable of triggering a light-induced and retinaldehyde cofactor dependent G-protein coupled receptor cascade, much like Opn4m studied in mammals. Opn4x appears to have a much weaker light-induced response.
- Lok, Corie (20 January 2011). "Vision science: Seeing without seeing". Nature 469 (7330): 284–5. Bibcode:2011Natur.469..284L. doi:10.1038/469284a. PMID 21248815.
- Jennifer Couzin-Frankel (2010). "Why Light Makes Migraines Worse - ScienceNOW". Retrieved 2011-04-03.
- Panda S, Nayak SK, Campo B, Walker JR, Hogenesch JB, Jegla T (January 2005). "Illumination of the melanopsin signaling pathway". Science 307 (5709): 600–4. Bibcode:2005Sci...307..600P. doi:10.1126/science.1105121. PMID 15681390.
- Yoshimura T, Nishio M, Goto M, Ebihara S (March 1994). "Differences in circadian photosensitivity between retinally degenerate CBA/J mice (rd/rd) and normal CBA/N mice (+/+)". Journal of Biological Rhythms 9 (1): 51–60. doi:10.1177/074873049400900105. PMID 7949306.
- Provencio I, Jiang G, De Grip WJ, Hayes WP, Rollag MD (January 1998). "Melanopsin: An opsin in melanophores, brain, and eye". Proc. Natl. Acad. Sci. U.S.A. 95 (1): 340–5. Bibcode:1998PNAS...95..340P. doi:10.1073/pnas.95.1.340. PMC 18217. PMID 9419377.
- Freedman MS, Lucas RJ, Soni B, Schantz MV, Munoz M, David-Gray Z, Foster R (April 1999). "Regulation of Mammalian Circadian Behavior by Non-rod, Non-cone, Ocular Photoreceptor". Science 284 (5413): 502–4. Bibcode:1999Sci...284..502F. doi:10.1126/science.284.5413.502. PMID 10205061.
- Provencio I, Rodrigues IR, Jiang G, Hayes WP, Moreira EF, Rollag MD (January 2000). "A Novel Human Opsin in the Inner Retina". J. Neurosci. 20 (2): 600–5. PMID 10632589.
- Berson DM, Dunn FA, Takao M (February 2002). "Phototransduction by retinal ganglion cells that set the circadian clock". Science 295 (5557): 1070–3. Bibcode:2002Sci...295.1070B. doi:10.1126/science.1067262. PMID 11834835.
- Qiu, X.; Kumbalasiri, T.; Carlson, M.; Wong, Y.; Krishna, V.; Provencio, I.; Berson, M. (Feb 2005). "Induction of photosensitivity by heterologous expression of melanopsin". Nature 433 (7027): 745–749. Bibcode:2005Natur.433..745Q. doi:10.1038/nature03345. ISSN 0028-0836. PMID 15674243.
- Tu DC, Zhang D, Demas J, Slutsky EB, Provencio I, Holy TE, Van Gelder RN (December 2005). "Physiologic diversity and development of intrinsically photosensitive retinal ganglion cells". Neuron 48 (6): 987–99. doi:10.1016/j.neuron.2005.09.031. PMID 16364902.
- Hattar S, Liao HW, Takao M, Berson DM, Yau KW (February 2002). "Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity". Science 295 (5557): 1065–70. Bibcode:2002Sci...295.1065H. doi:10.1126/science.1069609. PMC 2885915. PMID 11834834.
- Wong KY, Dunn FA, Berson DM (December 2005). "Photoreceptor adaptation in intrinsically photosensitive retinal ganglion cells". Neuron 48 (6): 1001–10. doi:10.1016/j.neuron.2005.11.016. PMID 16364903.
- Berson, M. (Aug 2007). "Phototransduction in ganglion-cell photoreceptors". Pflugers Archiv : European journal of physiology 454 (5): 849–855. doi:10.1007/s00424-007-0242-2. ISSN 0031-6768. PMID 17351786.
- Melyan Z, Tarttelin EE, Bellingham J, Lucas RJ, Hankins MW (February 2005). "Addition of human melanopsin renders mammalian cells photoresponsive". Nature 433 (7027): 741–5. Bibcode:2005Natur.433..741M. doi:10.1038/nature03344. PMID 15674244.
- Enezi J, Revell V, Brown T, Wynne J, Schlangen L, Lucas R. (august 2011). "A 'melanopic' spectral efficiency function predicts the sensitivity of melanopsin photoreceptors to polychromatic lights". Journal of Bological Rhythms 26 (4): 314–323. doi:10.1177/0748730411409719. PMID 21775290.
- Enezi J, Revell V, Brown T, Wynne J, Schlangen L, Lucas R., 'Measuring melanopic illuminance' http://lucasgroup.lab.ls.manchester.ac.uk/research/measuringmelanopicilluminance/
- Sakamoto K, Liu C, Kasamatsu M, Pozdeyev NV, Iuvone PM, Tosini G. Dopamine regulates melanopsin mRNA expression in intrinsically photosensitive retinal ganglion cells. Eur J Neurosci. 2005; 22: 3129–3136.
- Hannibal J, Fahrenkrug J (February 2004). "Target areas innervated by PACAP-immunoreactive retinal ganglion cells". Cell Tissue Res. 316 (1): 99–113. doi:10.1007/s00441-004-0858-x. PMID 14991397.
- Roecklein KA, Rohan KJ, Duncan WC, Rollag MD, Rosenthal NE, Lipsky RH, Provencio I (April 2009). "A missense variant (P10L) of the melanopsin (OPN4) gene in seasonal affective disorder". J Affect Disord 114 (1–3): 279–85. doi:10.1016/j.jad.2008.08.005. PMC 2647333. PMID 18804284.
- Panda S, Sato TK, Castrucci AM, Rollag MD, DeGrip WJ, Hogenesch JB, Provencio I, Kay SA (December 2002). "Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting". Science 298 (5601): 2213–6. doi:10.1126/science.1076848. PMID 12481141.
- Güler AD, Ecker JL, Lall GS, Haq S, Altimus CM, Liao H, Barnard AR, Cahill H, Badea TC, Zhao H, Hankins MW, Berson DM, Lucas RJ, Yau K, Hattar S (2008). "Melanopsin cells are the principal conduits for rod–cone input to non-image-forming vision". Nature 453 (7191): 102–5. Bibcode:2008Natur.453..102G. doi:10.1038/nature06829. PMC 2871301. PMID 18432195.
- Panda S, Provencio I, Tu DC, Pires SS, Rollag MD, Castrucci AM, Pletcher MT, Sato TK, Wiltshire T, Andahazy M, Kay SA, Van Gelder RN, Hogenesch JB (25 July 2003). "Melanopsin is required for non-image-forming photic responses in blind mice". Science 301 (5632): 525–7. Bibcode:2003Sci...301..525P. doi:10.1126/science.1086179. PMID 12829787.
- Czeisler CA, Shanahan TL, Klerman EB, Martens H, Brotman DJ, Emens JS, Klein T, Rizzo JF (January 1995). "Suppression of melatonin secretion in some blind patients by exposure to bright light". N. Engl. J. Med. 332 (1): 6–11. doi:10.1056/NEJM199501053320102. PMID 7990870.
- Arendt, Josephine (1 February 2006). "Chapter 15. The Pineal Gland and Pineal Tumours". Neuroendocrinology, Hypothalamus, and Pituitary,. Endotext.com. pp. an E–book edited by Ashley Grossman (chapter section: Melatonin Synthesis and Metabolism). Retrieved 2008-02-07. "Image forming vision (rods and cones) is not required ... for synchronising /phase shifting the circadian clock."
- Brown, TM, Gias C, Hatori M, Keding SR et al. (2010). "Melanopsin Contributions to Irradiance Coding in the Thalamo-Cortical Visual System". PLoS Biol 8 (12). doi:10.1371/journal.pbio.1000558.
- Bellingham J, Chaurasia SS, Melyan Z, Liu C, Cameron MA, Tarttelin EE, Iuvone PM, Hankins MW, Tosini G, Lucas RJ (July 2006). "Evolution of melanopsin photoreceptors: discovery and characterization of a new melanopsin in nonmammalian vertebrates". PLoS Biol. 4 (8): e254. doi:10.1371/journal.pbio.0040254. PMC 1514791. PMID 16856781.