Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin (types I, II, and III) in the rod and cone photoreceptor cells, respectively.

In humans, melanopsin is found in intrinsically photosensitive retinal ganglion cells (ipRGCs). It is also found in the iris of mice and primates. Melanopsin is also found in rats, amphioxus, and other chordates. ipRGCs are photoreceptor cells which are particularly sensitive to the absorption of short-wavelength (blue) visible light and communicate information directly to the area of the brain called the suprachiasmatic nucleus (SCN), also known as the central "body clock", in mammals. 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). According to one study, melanopsin has been found in eighteen sites in the human brain (outside the retinohypothalamic tract), intracellularly, in a granular pattern, in the cerebral cortex, the cerebellar cortex and several phylogenetically old regions, primarily in neuronal soma, not in nuclei. Melanopsin is also expressed in human cones. However, only 0.11% to 0.55% of human cones express melanopsin and are exclusively found in the peripheral regions of the retina. The human peripheral retina senses light at high intensities that is best explained by four different photopigment classes.

Melanopsin was discovered by Ignacio Provencio as a new 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, the cells involved in image-forming vision, 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 is encoded by the Opn4 gene 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.

Mammals have orthologous melanopsin genes named Opn4, which are approximately 50-55% conserved. However, non-mammalian vertebrates, including chickens, zebrafish, and Xenopus laevis, have two versions of the melanopsin gene: a mammalian-like Opn4m and a separate Opn4x from a lineage that diverged from Opn4m about 360 million years ago. Both versions are functional in these vertebrates. Mammals lost the gene Opn4x relatively early in their evolution, leading to a general reduction in photosensory capability. The loss is estimated to have occurred during the time in which nocturnal mammals were evolving.

The human melanopsin gene, opn4, is expressed in ipRGCs, which comprises only 1-2% of RGCs 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. 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, rhodopsin and encephalopsin.

Melanopsin, like all other animal opsins (e.g. rhodopsin), is a G-protein-coupled receptor (GPCR). The melanopsin protein has an extracellular N-terminal domain, an intracellular C-terminal domain, and seven alpha helices spanning through the plasma membrane. The seventh helix has a lysine that corresponds to Lys296^7.43 in cattle rhodopsin and that is conserved in almost all opsins. This lysine binds covalently retinal via a Schiff-base, which makes melanopsin light sensitive. In fact this is abolished if the lysine is replaced by an alanine.

Melanopsin is more closely related to invertebrate visual opsins, which are rhabdomeric opsin, than to vertebrate visual opsins, which are cliary opsins. This is also reflected by the downstream signaling cascade, melanopsin couples in ipRGCs to the G-proteins G(q), G(11), and G(14), which are all of the G(q)-type. In fact, they can functionally replace each other, as a knocking out only two of them has no phenotypical effect. The G-proteins activate the phospholipase C PLCB4, which causes the TRP-channels TRPC6 and TRPC7 mediate to open so that the cell depolarizes. This is like in the photoreceptor cells of the Drosophila eye, and in contrast to the vertebrate rod and cone cells, where phototransduction eventually makes the cells hyperpolarize. Like other rhabdomeric opsins, Melanopsin has intrinsic photoisomerase activity.