Melanopsin
Encyclopedia
Melanopsin is a photopigment
found in specialized photosensitive ganglion cell
s 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 vertebrate
s. 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.
in Japan discovered in 1994 that although the phase response curve
s 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.
In 2002, Samer Hattar and his colleagues provided evidence supporting prior theories that melanopsin is the photopigment responsible for mammalian SCN entrainment. After cloning the melanopsin full length cDNA, Hattar was able to use fluorescent immunocytochemistry
to visualize melanopsin distribution throughout the rat retina. Results of this experiment 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).
Further studies from Berson's lab have concluded that 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.
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 (peak absorption ~480 nm), while it also has an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths.
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.
s 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 rhythm
s). 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.
Mutation of a gene expressing melanopsin has been implicated in the risk of having Seasonal Affective Disorder
(SAD).
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.
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.
Photopigment
Photopigments are unstable pigments that undergo a chemical change when they absorb light. The term is generally applied to the non-protein chromophore moiety of photosensitive chromoproteins, such as the pigments involved in photosynthesis and photoreception...
found in specialized photosensitive ganglion cell
Photosensitive ganglion cell
Photosensitive ganglion cells, also called photosensitive Retinal Ganglion Cells , intrinsically photosensitive Retinal Ganglion Cells or melanopsin-containing ganglion cells, are a type of neuron in the retina of the mammalian eye.They were discovered in the early 1990sand are, unlike other...
s of the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
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
Opsin
Opsins are a group of light-sensitive 35–55 kDa membrane-bound G protein-coupled receptors of the retinylidene protein family found in photoreceptor cells of the retina. Five classical groups of opsins are involved in vision, mediating the conversion of a photon of light into an electrochemical...
, a retinylidene protein
Retinylidene protein
Retinylidene proteins are a family of proteins that use retinal as chromophore for light reception. Proteins of this family are also called opsins...
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
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
pain.
Melanopsin differs from other opsin photopigments in vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s. In fact, it resembles invertebrate
Invertebrate
An invertebrate is an animal without a backbone. The group includes 97% of all animal species – all animals except those in the chordate subphylum Vertebrata .Invertebrates form a paraphyletic group...
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
Photoisomerase
A photoisomerase is a protein in the eye that is responsible for isomerizing photopigments.In order for the eye to function propertly, a special chemical called a chromophore is bound to a protein known as an opsin. When a photon strikes the chromophore, it changes shape . It is this change in...
activity, and to signal through a G-protein of the Gq family.
Discovery and function
Takashi Yoshimura and Shizufumi Ebihara of Nagoya UniversityNagoya University
Nagoya University is one of the most prestigious universities in Japan. It can be seen in the several rankings such as shown below.-General Rankings:...
in Japan discovered in 1994 that although the phase response curve
Phase response curve
A phase response curve illustrates the transient change in the cycle period of an oscillation induced by a perturbation as a function of the phase at which it is received...
s 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
Ignacio Provencio
Ignacio Provencio is an American neuroscientist and the discoverer of melanopsin, a photopigment found in specialized photosensitive ganglion cells of the mammalian retina...
and his colleagues in 1998, in the specialized light sensitive cells of frog skin. In 1999, Russell G. Foster
Russell G. Foster
Russell Grant Foster, FRS is a British professor of circadian neuroscience, currently based at Brasenose College at the University of Oxford. He and his group are credited with the discovery of the non-rod, non-cone, photosensitive ganglion cells in the mammalian retina which provide input to the...
showed that entrainment
Entrainment (chronobiology)
Entrainment, within the study of chronobiology, occurs when rhythmic physiological or behavioral events match their period and phase to that of an environmental oscillation. A common example is the entrainment of circadian rhythms to the daily light–dark cycle, which ultimately is determined by...
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
David Berson
David M. Berson is Professor of Medical Science at Brown University. He helped lead the way in the discovery of a third class of mammalian photoreceptors by providing the first electrophysiological recordings from intrinsically photosensitive retinal ganglion cells.-External links:*Critical Review ...
and colleagues at Brown University
Brown University
Brown University is a private, Ivy League university located in Providence, Rhode Island, United States. Founded in 1764 prior to American independence from the British Empire as the College in the English Colony of Rhode Island and Providence Plantations early in the reign of King George III ,...
. They also showed that these responses persisted when pharmacological agents blocked synaptic
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
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
Photosensitive ganglion cell
Photosensitive ganglion cells, also called photosensitive Retinal Ganglion Cells , intrinsically photosensitive Retinal Ganglion Cells or melanopsin-containing ganglion cells, are a type of neuron in the retina of the mammalian eye.They were discovered in the early 1990sand are, unlike other...
(ipRGCs). They constitute a third class of photoreceptor cells in the mammalian retina, beside the already known rod
Rod cell
Rod cells, or rods, are photoreceptor cells in the retina of the eye that can function in less intense light than can the other type of visual photoreceptor, cone cells. Named for their cylindrical shape, rods are concentrated at the outer edges of the retina and are used in peripheral vision. On...
and cone
Cone cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...
photoreceptors.
In 2002, Samer Hattar and his colleagues provided evidence supporting prior theories that melanopsin is the photopigment responsible for mammalian SCN entrainment. After cloning the melanopsin full length cDNA, Hattar was able to use fluorescent immunocytochemistry
Immunocytochemistry
Immunocytochemistry is a common laboratory technique that uses antibodies that target specific peptides or protein antigens in the cell via specific epitopes. These bound antibodies can then be detected using several different methods. ICC allows researchers to evaluate whether or not cells in a...
to visualize melanopsin distribution throughout the rat retina. Results of this experiment 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
X-gal
X-gal is an organic compound consisting of galactose linked to a substituted indole. The compound was synthesized by Jerome Horwitz and collaborators in Detroit, MI, in 1964. The formal chemical name is often shortened to less accurate but also less cumbersome phrases such as bromochloroindoxyl...
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
Retinohypothalamic tract
The retinohypothalamic tract is a photic input pathway involved in the circadian rhythms of mammals. The origin of the retinohypothalamic tract is the intrinsically photosensitive retinal ganglion cells , which contain the photopigment melanopsin...
(RHT).
Further studies from Berson's lab have concluded that melanopsin-containing ganglion cells exhibit both light and dark adaptation
Adaptation (eye)
In ocular physiology, adaptation is the ability of the eye to adjust to various levels of darkness and light.-Efficacy:The human eye can function from very dark to very bright levels of light; its sensing capabilities reach across nine orders of magnitude. This means that the brightest and the...
, 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.
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 (peak absorption ~480 nm), while it also has an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths.
Dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
(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.
Mechanism
When light activates the melanopsin signaling system, the melanopsin-containing ganglion cells discharge nerve impulses, which are conducted through their axonAxon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s 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
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
of the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
(the master pacemaker of circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
s). 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.
Mutation of a gene expressing melanopsin has been implicated in the risk of having Seasonal Affective Disorder
Seasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...
(SAD).
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 knockoutGene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
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
Pupillary reflex
The pupillary light reflex is a reflex that controls the diameter of the pupil, in response to the intensity of light that falls on the retina of the eye, thereby assisting in adaptation to various levels of darkness and light, in addition to retinal sensitivity...
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.
Distribution in different species
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 irisIris (anatomy)
The iris is a thin, circular structure in the eye, responsible for controlling the diameter and size of the pupils and thus the amount of light reaching the retina. "Eye color" is the color of the iris, which can be green, blue, or brown. In some cases it can be hazel , grey, violet, or even pink...
muscle of the eye, deep brain regions, the pineal gland
Pineal gland
The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...
, 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.