Picking Out the Prime Suspect

Abstract

NEUROSCIENCE An ancient cellular mechanism drives the rhythms of the body, and to ensure that this biological clock is in tune with the 24-hour cycles of the Earth, it can be reset by light or by temperature. How temperature resets the clock in mammals is not known, but now Provencio et al. have provided a strong candidate for the pigment that captures light to reset the mammalian clock. There have been several suspects along the way. The most obvious pigments in the eye, the opsins in the rods and cones of the retina (which form visual images), are surprisingly unimportant for mediating light effects on circadian rhythms: Light easily resets the clocks of mice with no rods or cones and of people who are completely blind. Another pair of suspects has been the cryptochromes, flavin-based pigments that absorb blue light and are present in retinal ganglion and inner nuclear cells, but recent evidence has knocked cryptochromes almost entirely out of the line-up. The phenotype of mice missing both cryptochrome 1 and 2 suggests that cryptochromes are not required for entrainment of the circadian rhythm, and their interaction with other clock components does not require light, as would be expected if they were light receptors. The new prime suspect is melanopsin, an opsin found only in the cells of the mammalian inner retina. Melanopsin is much more like invertebrate opsins than mammalian ones, including the substitution of an aromatic residue for a Schiff's base counterion, which in the usual mammalian opsins allows local regeneration of the chromophore. The melanopsin in retinal ganglion and amacrine cells far away from the chromophore-regenerating retinal pigment epithelium would require such local regeneration for function. To add to the argument, these melanopsin-containing cells have the same frequency and distribution as the retinal cells that project directly to the suprachiasmatic nucleus, the site of the clock. Finally, the peak of the circadian light response is at a wavelength expected from an opsin-based photopigment (like melanopsin), rather than a flavin-based photopigment. At this point, the evidence remains circumstantial and several other pigments in the retina must remain in town for questioning. Nonetheless, melanopsin is emerging as a likely culprit as a receptor for the light that keeps mammalian bodies in tune and in time.— KK J. Neurosci. 20 , 600 (2000).