1 Non-image forming, irradiance-dependent responses mediated by the human eye include synchronisation of the circadian axis and suppression of pineal melatonin production The retinal photopigment(s) transducing these light responses in humans have not been characterised 2 Using the ability of light to suppress nocturnal melatonin production, we aimed to investigate its spectral sensitivity and produce an action spectrum Melatonin suppression was quantified in 22 volunteers in 215 light exposure trials using monochromatic light (30 min pulse administered at circadian time (CT) 16-18) of different wavelengths (lambda(max) 424, 456, 472, 496, 520 and 548 nm) and irradiances (07-650 microW cm(-2)) 3 At each wavelength, suppression of plasma melatonin increased with increasing irradiance Irradiance-response curves (IRCs) were fitted and the generated half-maximal responses (IR(50)) were corrected for lens filtering and used to construct an action spectrum 4 The resulting action spectrum showed unique short-wavelength sensitivity very different from the classical scotopic and photopic visual systems The lack of fit (r(2) or =073) Of these, the best fit was to the rhodopsin template with lambda(max) 459 nm (r(2) = 074) 5 Our data strongly support a primary role for a novel short-wavelength photopigment in light-induced melatonin suppression and provide the first direct evidence of a non-rod, non-cone photoreceptive system in humans

An action spectrum for melatonin suppression: evidence for a novel non‐rod, non‐cone photoreceptor system in humans

The basic physiology and pathophysiology of melatonin

Melatonin, the major hormone produced by the pineal gland, displays characteristic daily and seasonal patterns of secretion. These robust and predictable rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes in photoperiodic species. In mammals, the nighttime production of melatonin is mainly driven by the circadian clock, situated in the suprachiasmatic nucleus of the hypothalamus, which controls the release of norepinephrine from the dense pineal sympathetic afferents. The pivotal role of norepinephrine in the nocturnal stimulation of melatonin synthesis has been extensively dissected at the cellular and molecular levels. Besides the noradrenergic input, the presence of numerous other transmitters originating from various sources has been reported in the pineal gland. Many of these are neuropeptides and appear to contribute to the regulation of melatonin synthesis by modulating the effects of norepinephrine on pineal biochemistry. The aim of this review is firstly to update our knowledge of the cellular and molecular events underlying the noradrenergic control of melatonin synthesis; and secondly to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis. This information reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism. This also clarifies the role of these various inputs in the seasonal variation of melatonin synthesis and their subsequent physiological function.

Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters

Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways.

In mammals, ocular photoreceptors mediate an acute inhibition of pineal melatonin by light. The effect of rod and cone loss on this response was assessed by combining the rd mutation with a transgenic ablation of cones (cl) to produce mice lacking both photoreceptor classes. Despite the loss of all known retinal photoreceptors, rd/rd cl mice showed normal suppression of pineal melatonin in response to monochromatic light of wavelength 509 nanometers. These data indicate that mammals have additional ocular photoreceptors that they use in the regulation of temporal physiology.

https://science.sciencemag.org/content/sci/284/5413/505.full.pdf

Robert Y. Moore

Papers

Pineal N-acetyltransferase and hydroxyindole-O-methyltransferase: control by the retinohypothalamic tract and the suprachiasmatic nucleus.