The melanopsin system: Phototransduction, projections, functions, and clinical implications

The melanopsin system consists of retinal ganglion cells containing the photopigment melanospin, which are directly activated by light in the absence of inputs from the photoreceptors. These intrinsically photosensitive retinal ganglion cells (ipRGCs) detect environmental brightness; combine their direct, melanospin-triggered photoresponses with signals derived from rods and cones; and project to several targets in the diencephalon and midbrain. Via these projections, the melanospin system mediates several non-imaging-forming visual functions, including light entrainment of circadian rhythms and pupillary responses to light. The discovery of the melanopsin system explained the preservation of normal circadian rhythms, relative preservation of pupillary reflexes, and excessive light sensitivity in patients with visual loss due to disorders affecting the photoreceptors. The melanopsin-containing ipRGCs are relatively spared in inherited mitochondrial optic neuropathies, may be selectively affected in glaucoma, and may trigger photophobia in patients with migraine. Polymorphisms in the melanospin (opsin 4, Opn4) gene are associated with seasonal affective disorder. The functional organization of the melanopsin system and its implications in disease have been recently reviewed.1,–,7 ### Intrinsically photosensitive retinal ganglion cells. Melanopsin (also called opsin 4, Opn4) is a photopigment that was first identified in frog skin and was thereafter detected in a small subpopulation of retinal ganglion cells in vertebrates.8 The ipRGCs respond to light stimulation with depolarization in the absence of any synaptic input from rods and cones; hence their designation as intrinsically photosensitive.1,9 The ipRGCs combine their direct, melanospin-triggered photoresponses with signals derived from rods and cones and project to several targets in the diencephalon and midbrain involved in circadian rhythms and pupil responses to light (figure) The ipRGCs constitute a small percentage of ganglion cells; in each human eye, up to 3,000 out of ∼1.5 million retinal ganglion cells stain positively for melanopsin10; these cells are more concentrated …