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Opsin 4 (melanopsin)
Melanopsin is a photopigment found in specialized photosensitive ganglion cells of the retina that are involved in the regulation of circadian rhythms, pupillary reflex, and other non-visual responses to light. In structure, melanopsin is an opsin, a retinylidene protein variety of G-protein-coupled receptor.
Melanopsin, atypical in vertebrates, functionally resembles invertebrate opsins, including an apparent intrinsic photoisomerase activity. It is presumed that melanopsin signals through a G-protein of the Gq family, as invertebrate opsins are known to do, but this is not firmly established.
 Discovery and function
Melanopsin was originally discovered in 1998 in specialized light-sensitive cells of frog skin by Dr. Ignacio Provencio and his colleagues. In 1999 Dr. Russell Foster showed that a third class of photoreceptor existed in mammalian eyes. In 2000, Provencio showed that mammals, including humans, also produce melanopsin and that it is found only in a rare subtype of retinal ganglion cells, the output cells of the retina.
They also showed that these responses persisted when pharmacological agents blocked synaptic communication in the retina, and when single melanopsin ganglion cells were physically isolated from other retinal cells. These findings showed that melanopsin ganglion cells are intrinsically photosensitive, and thus constitute a third class of photoreceptors in the mammalian retina, joining the better known rod and cone photoreceptors.
Further studies from Berson's lab have concluded that melanopsin 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 ganglion cells contribute to various reflexive responses of the brain and body to the presence of (day)light.
Melyan et al in England in 2005 reported rendering a mouse paraneuronal cell line (Neuro-2a), which normally is not photosensitive, 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, while it also has an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths.
These targets include the olivary pretectal nucleus (a center responsible for controlling the pupil of the eye) and, through the retinohypothalamic tract (RHT), the suprachiasmatic nucleus of the hypothalamus (the master pacemaker of circadian rhythms).
Melanopsin 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 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, but mice lacking rods and cones still exhibit circadian entrainment. The pupillary reflex is also retained in mice lacking rods and cones but has severely reduced sensitivity, identifying a crucial input from the rods and cones.
Blind people who entrain to the 24-hour light/dark cycle have eyes with functioning retinas including the operative non-visual light-sensitive cells which convey their signals to the "circadian clock" via the retinohypothalamic tract.
 Distribution in different species
Melanopsin has a very similar pattern of tissue distribution among all mammals studied so far, including rodents, monkeys, and humans. Specifically, melanopsin is expressed only in the retina, and only in 1-2% of the ganglion cells.
In non-mammalian vertebrates, however, such as birds, fish and amphibians, melanopsin is found in certain other retinal cells, and also outside the retina in structures known or presumed to be directly photosensitive, such as the iris muscle of the eye, deep brain regions, the pineal gland, and the skin.
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