Melanopsin

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.^[1] A melanopsin based receptor has been linked to the association between light sensitivity and migraine pain.^[2]

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,^[3] and to signal through a G-protein of the Gq family.

Discovery

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.^[4] 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.^[4]

Melanopsin was originally discovered by Ignacio Provencio and his colleagues in 1998, in the specialized light sensitive cells of frog skin.^[5] 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.^[6] In 2000, Provencio determined that melanopsin was expressed only in the inner retina of mammals, including humans, and that it mediated nonvisual photoreceptive tasks.^[7]

The first recordings of light responses from melanopsin-containing ganglion cells were obtained by David Berson and colleagues at Brown University.^[8] 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.^[8] These findings showed that melanopsin-containing ganglion cells are intrinsically photosensitive,^[9] and they were thus named intrinsically photosensitive Retinal Ganglion Cells (ipRGCs).^[10] They constitute a third class of photoreceptor cells in the mammalian retina, beside the already known rod and cone photoreceptors.

Function

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).^[11]

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.^[12] 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),^[13] while it also has an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths.^[14]

Melanopsin photoreceptors are sensitive to a range of light wavelengths.^[15] 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.^[16]

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.^[17]

Mechanism

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).^[11] 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).^[18] Melanopsin-containing ganglion cells also receive input from rods and cones that modifies or adds to the input to these pathways.

Clinical significance

Mutation of a gene expressing melanopsin has been implicated in the risk of having Seasonal Affective Disorder (SAD).^[19]

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.^[20] Entrainment is lost entirely when melanopsin-expressing cells are killed, as these cells are also required for transmission of rod-cone light information.^[21] Mice lacking rods and cones still exhibit circadian entrainment, but also show reduced response to light.^[22] Such mice can, however, distinguish between visual patterns.^[1] 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.^[22] Without melanopsin, rods, and cones, mice fail to entrain to circadian rhythms and the pupillary reflex is lost.^[22]

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.^[23] These people have intact retinohypothalamic tracts that allow signaling from the ipRGCs to the suprachiasmatic nucleus.^[24] 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.^[25]

Species distribution

Melanopsin genes have been described in all vertebrate classes, and an extra melanopsin ortholog has been discovered in fish, bird, and amphibian genomes.^[26] 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.^[11] 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.^[26]

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.^[26]

References