Melanopsin—Shedding Light on the Elusive Circadian Photopigment

Abstract

Circadian photoentrainment is the process by which the brain's internal clock becomes synchronized with the daily external cycle of light and dark. In mammals, this process is mediated exclusively by a novel class of retinal ganglion cells that send axonal projections to the suprachiasmatic nuclei (SCN), the region of the brain that houses the circadian pacemaker. In contrast to their counterparts that mediate image-forming vision, SCN-projecting RGCs are intrinsically sensitive to light, independent of synaptic input from rod and cone photoreceptors. The recent discovery of these photosensitive RGCs has challenged the long-standing dogma of retinal physiology that rod and cone photoreceptors are the only retinal cells that respond directly to light and has explained the perplexing finding that mice lacking rod and cone photoreceptors can still reliably entrain their circadian rhythms to light. These SCN-projecting RGCs selectively express melanopsin, a novel opsin-like protein that has been proposed as a likely candidate for the photopigment in these cells. Research in the past three years has revealed that disruption of the melanopsin gene impairs circadian photoentrainment, as well as other nonvisual responses to light such as the pupillary light reflex. Until recently, however, there was no direct demonstration that melanopsin formed a functional photopigment capable of catalyzing G-protein activation in a light-dependent manner. Our laboratory has recently succeeded in expressing melanopsin in a heterologous tissue culture system and reconstituting a pigment with the 11-cis-retinal chromophore. In a reconstituted biochemical system, the reconstituted melanopsin was capable of activating transducin, the G-protein of rod photoreceptors, in a light-dependent manner. The absorbance spectrum of this heterologously expressed melanopsin, however, does not match that predicted by previous behavioral and electophysiological studies. Although melanopsin is clearly the leading candidate for the elusive photopigment of the circadian system, further research is needed to resolve the mystery posed by its absorbance spectrum and to fully elucidate its role in circadian photoentrainment. KeywordsMelanopsin; Circadian rhythm; Photoentrainment; Opsin SUNRISE, SUNSET, SUNRISE, SUNSET, SWIFTLY FLY THE YEARSEven as Tevyes laments the inexorable passage of time in these lyrics from Fiddler on the Roof, he concedes that the solar cycle of day and night has been a fact of life on Earth since the dawn of evolution. In fact, most living organisms-from cyanobacteria to man-have adapted their physiology and behavior to this daily cycle (Devlin and Kay, 2001;Dunlap, 1999;Harmer et al., 2001;Young and Kay, 2001 , 1972;Ralph et al., 1990). Like an old watch, however, this internal clock does not keep perfect time, and it must be reset each morning by dawn's early light, a process termed circadian photoentrainment. This process also allows the clock to be reset following travel across time zones and to adjust to seasonal differenc...

Phototransduction in ganglion-cell photoreceptors

“…These intrinsically photosensitive RGCs (ipRGCs) are now recognized as playing key roles in synchronizing circadian rhythms to the day-night cycle, mediating the pupillary response to light, and modulation of melatonin release by the pineal gland. Many aspects of this rapidly developing story have been thoroughly summarized elsewhere [4,6,14,16,31,44,54,61]. The reader is referred to these reviews for background on the intellectual origins of the discovery of melanopsin and the ipRGCs, on their structure and physiology, and on their contribution to circadian photoentrainment and other nonimage-forming visual functions.…”

Iii-1 : La Retine : Organisation Schematique

“…Un dysfonctionnement du gène codant pour la mélanopsine entraîne des perturbations du rythme circadien et du réflexe pupillaire [Brown RL, Robinson PR, 2004], [Guler AD et al, 2007].…”

Day/night variations in membrane bound leucyl-2-naphthylamide hydrolysing activity in rat anterior hypothalamus, pituitary and retina

“…This nucleus is integrated in a photoneuroendocrine circuit that includes the retina and other selected regions of the neuroendocrine system. Firstly, nerve impulses are generated in the retinal ganglion cells through a novel opsin-like protein which has been recently proposed as a likely candidate for the photopigment in these cells (Brown & Robinson 2004). Subsequently, they reach the suprachiasmatic nuclei of the anterior Correspondence: Garbiñ e Arechaga, Departamento Ciencias de la Salud, Facultad de Ciencias Experimentales, Universidad de Jaén.…”