1. Department of Neuroscience, Box 1953, Brown University, Providence, Rhode Island 02912-1953, USA
2. Department of Anatomy, Physiology and Genetics and the Graduate Program in Neuroscience, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA
3. These authors contributed equally to this work
4. Current address: Department of Biology, University of Virginia, Charlottesville, Virginia 22904, USA

Correspondence to: David M. Berson¹ Correspondence and requests for materials should be addressed to D.B. (Email: David_Berson@brown.edu).

Abstract

Melanopsin^{1, 2, 3, 4, 5, 6, 7, 8} has been proposed to be the photopigment of the intrinsically photosensitive retinal ganglion cells (ipRGCs)^{7, 8, 9, 10, 11, 12, 13, 14, 15}; these photoreceptors of the mammalian eye drive circadian and pupillary adjustments through direct projections to the brain^{5, 6, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18}. Their action spectrum ( _max 480 nm) implicates an opsin¹⁰ and melanopsin is the only opsin known to exist in these cells. Melanopsin is required for ipRGC photosensitivity¹³ and for behavioural photoresponses that survive disrupted rod and cone function^{14, 17}. Heterologously expressed melanopsin apparently binds retinaldehyde and mediates photic activation of G proteins¹⁹. However, its amino-acid sequence differs from vertebrate photosensory opsins^{1, 20} and some have suggested that melanopsin may be a photoisomerase, providing retinoid chromophore to an unidentified opsin^{3, 20}. To determine whether melanopsin is a functional sensory photopigment, here we transiently expressed it in HEK293 cells that stably expressed TRPC3 channels. Light triggered a membrane depolarization in these cells and increased intracellular calcium. The light response resembled that of ipRGCs, with almost identical spectral sensitivity ( _max 479 nm). The phototransduction pathway included Gq or a related G protein, phospholipase C and TRPC3 channels. We conclude that mammalian melanopsin is a functional sensory photopigment, that it is the photopigment of ganglion-cell photoreceptors, and that these photoreceptors may use an invertebrate-like phototransduction cascade.

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