Action Spectrum for Melatonin Regulation in Humans: Evidence for a Novel Circadian Photoreceptor
George C. Brainard,John P. Hanifin,Jeffrey M. Greenson, Brenda Byrne, Gena Glickman, Edward Gerner, a Mark D. Rollag
Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and 2Department of Anatomy, Physiology and Genetics, Uniformed Services University of Health Sciences, Bethesda, Maryland 20814
The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for lightinduced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects’ pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence–response curves (R2 0.81–0.95). The action spectrum constructed from these data fit an opsin template (R2 0.91), which identifies 446–477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.
Key words: melatonin; action spectrum; circadian; wavelength; light; pineal gland; neuroendocrine; photoreception; photopigment; human
The action spectrum presented here matches a vitamin A1- retinaldehyde photopigment template that supports the hypothesis that one of the new opsin photopigment candidates provides primary photic input for melatonin regulation in humans. The molecular identification of candidate opsin or non-opsin photoreceptors and their localization in the retina and/or neural components of the circadian system make them well suited to act as circadian phototransducers. However, functional data confirming any of these molecules as having a direct role in mammalian circadian photoreception is currently lacking. Furthermore, caution should be exercised in generalizing results from plants, insects, fish, amphibians, and rodents to humans. Are the effects of light on melatonin suppression relevant to general circadian regulation? Studies have shown that hamsters have a higher intensity threshold for light-induced phase-shifts of wheel-running rhythms than for melatonin suppression (Nelson and Takahashi, 1991). Recently, however, a study on humans showed that the 50% response sensitivity for circadian phase shifting (119 lux) was only slightly higher than that for melatonin suppression (106 lux) with white light (Zeitzer et al., 2000). It is possible that there are separate photoreceptors for mediating circadian entrainment versus acute suppression of melatonin. It is reasonable, however, to hypothesize that a variety of nonvisual effects of light, such as melatonin suppression, entrainment of circadian rhythms, and possibly some clinical responses to light, are mediated by a shared photoreceptor system. Additional experiments are needed to test this hypothesis. In general, relatively high light illuminances ranging from 2500 to 12,000 lux are used for treating winter depression, selected sleep disorders, and circadian disruption (Wetterberg, 1993; Lam, 1998). Although these light levels are therapeutically effective, some patients complain that they produce side effects of visual glare, visual fatigue, photophobia, ocular discomfort, and headache. Determining the action spectrum for circadian regulation may lead to improvements in light therapy. Total illuminances for treating a given disorder can be reduced as the wavelength emissions of the therapeutic equipment are optimized. Modern industrialized societies use light extensively in homes, schools, work places, and public facilities to support visual performance, visual comfort, and aesthetic appreciation within the environment. Given that light is also a powerful regulator of the human circadian system, future lighting strategies will need to provide illumination for human visual responses, as well as homeostatic responses. The action spectrum presented here suggests that there are separate photoreceptors for visual and circadian responses to light in humans. Hence, new approaches to architectural lighting may be needed to optimally stimulate both the visual and circadian systems. In conclusion, this study characterizes the wavelength sensitivity of the ocular photoreceptor system for regulating the human pineal gland by establishing an action spectrum for light-induced melatonin suppression. The results identify the 446–477 nm portion of the spectrum as the most potent wavelengths providing circadian input for regulating melatonin secretion. These data suggest that the primary photoreceptor system for melatonin suppression is distinct from the rod and cone photoreceptors for vision. Finally, this action spectrum suggests that there is a novel retinaldehyde photopigment that mediates human circadian photoreception. These findings open the door for optimizing the use of light in both therapeutic and architectural applications
Whole study of the impact of light on the suppression of melatonin secretion can be read here
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