Illumination of the Melanopsin Signaling Pathway

Abstract

In mammals, a small population of intrinsically photosensitive retinal ganglion cells (ipRGCs) plays a key role in the regulation of nonvisual photic responses, such as behavioral responses to light, pineal melatonin synthesis, pupillary light reflex, and sleep latency. These ipRGCs also express melanopsin (Opn4), a putative opsin-family photopigment that has been shown to play a role in mediating these nonvisual photic responses. Melanopsin is required for the function of this inner retinal pathway, but its precise role in generating photic responses has not yet been determined. We found that expression of melanopsin in Xenopus oocytes results in light-dependent activation of membrane currents through the Gα_q/Gα₁₁ G protein pathway, with an action spectrum closely matching that of melanopsin-expressing ipRGCs and of behavioral responses to light in mice lacking rods and cones. When coexpressed with arrestins, melanopsin could use all-trans-retinaldehyde as a chromophore, which suggests that it may function as a bireactive opsin. We also found that melanopsin could activate the cation channel TRPC3, a mammalian homolog of the Drosophila phototransduction channels TRP and TRPL. Melanopsin therefore signals more like an invertebrate opsin than like a classical vertebrate rod-and-cone opsin.