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. Species distribution Mammals have orthologous melanopsin genes named Opn4m, which are derived from one branch of the Opn4 family, and are approximately 50-55% conserved. However, non-mammalian vertebrates, including chickens and zebrafish, have another version of the melanopsin gene, Opn4x, which appears to have a distinct lineage that diverged from Opn4m about 360 million years ago. Mammals lost the gene Opn4x relatively early in their evolution, leading to a general reduction in photosensory capability. It is thought that this event can be explained by the fact that this occurred during the time in which nocturnal mammals were evolving. Structure 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 extarcellular 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 Lys2967.43 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