Melanopsin and mechanisms of non-visual ocular photoreception

Abstract

In addition to rods and cones, the mammalian eye contains a third class of photoreceptor, the intrinsically photosensitive retinal ganglion cell (ipRGC). ipRGCs are heterogeneous irradiance-encoding neurons that primarily project to non-visual areas of the brain. Characteristics of ipRGC light responses differ significantly from those of rod and cone responses, including depolarization to light, slow on- and off-latencies, and relatively low light sensitivity. All ipRGCs use melanopsin (Opn4) as their photopigment. Melanopsin resembles invertebrate rhabdomeric photopigments more than vertebrate ciliary pigments and uses a G(q) signaling pathway, in contrast to the G(t) pathway used by rods and cones. ipRGCs can recycle chromophore in the absence of the retinal pigment epithelium and are highly resistant to vitamin A depletion. This suggests that melanopsin employs a bistable sequential photon absorption mechanism typical of rhabdomeric opsins.

FIGURE 1.

ipRGC subtypes. Shown is an illustration of the morphologic and molecularly defined subtypes of ipRGCs (M1–M5 and M1 Brn3b transcription factor-positive and -negative) with neural projections, including the SCN, OPN, lateral geniculate nucleus (LGN), the IGLs of the geniculate nucleus, and the superior colliculus (SC).

FIGURE 2.

Structural relationship of melanopsin to other opsins. A, dendrogram of the relatedness of melanopsin (Opn4m and Opn4x) to other members of the opsin family demonstrating the close relationship of melanopsin to rhapdomeric opsins. MWS, middle wavelength-sensitive; SWS, short wavelength-sensitive; LWS, long wavelength-sensitive; RGR, retinal G-protein-coupled receptor. B, two-dimensional diagram of human melanopsin based on the structures of bovine rhodopsin (34, 49) and squid rhodopsin (83). Amino acids in white are commonly used in sequence comparisons within and between species. Highlighted amino acids include the retinal attachment site in orange (Lys-300), the two proposed Schiff base counterions in black (Tyr-106 and Glu-175), and a rhabdomere-like G-protein specificity sequence in black (Ala-268–Lys-276). C- and N-terminal structures of rhodopsins are not understood as well as the core transmembrane domain.

FIGURE 3.

Summary of chromophore recycling steps. Illustrated are steps for ciliary (A) and rhabdomeric (B) photoreceptor photocycles. Differences between a sequential bistable mechanism of chromophore regeneration seen in rhabdomeric photoreceptors and the thermally unstable activation of opsins in ciliary photoreceptors are illustrated. A blue lambda indicates light activation of opsin from the ground state to meta-state and conversion of the retinoid from the cis- to trans-conformation. A red lambda indicates the sequential absorption of a photon at a second wavelength that converts the meta-state to the ground state and re-isomerizes the retinoid back to the cis-conformation. Note that rhabdomeric photoreceptors often use alternative retinoids such as 11-cis-3-hydroxyretinal (3-OH-11-cis-retinal) in Drosophila used in the example above.

FIGURE 4.

Potential models for cell-autonomous and non-autonomous melanopsin chromophore recycling. A, three potential models for cell-autonomous chromophore recycling, including photoreversal, intrinsic dark isomerase, and second isomerase mechanisms. These mechanisms are not mutually exclusive. B, model for non-autonomous pigment recycling using Müller glial-based recycling. X indicates block to LRAT or RPE65, neither of which disrupts ipRGC function. Anatomic structures shown include the RPE, photoreceptor layer (PRL), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), IPL, ganglion cell layer (GCL), and optic fiber layer (OFL).