The actions of melatonin in peripheral tissues may be direct ones on the transcription, translation, or posttranslational alterations of cellular components such as enzymes and other proteins, or may take place through effects on the endogenous oscillator of the cell. Many peripheral tissues have their own oscillators that operate along the same mechanistic lines of the simple model shown in Figure 1B. These oscillators, which have varying degrees of autonomy from the SCN central clock, have been characterized in the adrenal cortex, pancreatic islets and the exocrine pancreas, adipose tissue, liver, heart, blood vessels, and stomach, among others. The adrenal cortex is one example of a tissue in which melatonin appears to act in the context of the cell’s oscillator.
Fig1. Regulation of melatonin synthesis. A. As described in Figure 2, light interacts with an intrinsically photosensitive retinal ganglion cell (ipRGC), the axon of which passes along the retinal-hypothalamic tract (RHT) and terminates on a neuron of the suprachiasmatic nucleus (SCN). The SCN neuron releases γ-amino-butyric acid (GABA; red) which inhibits the firing of the neuron of the paraventricular cell (PVN) of the hypothalamus. In the absence of light this cell releases glutamate which stimulates the firing of the PVN neuron so that the signal continues through the intermediolateral cell column (ILCC) neuron to the neurons of the superior cervical ganglion (SCG). These neurons release norepinephrine (NE) which interacts with its β-adrenergic receptor to stimulate intracellular cyclic AMP levels, leading to increased synthesis and translation of mRNA encoding N-acetyltransferase (AANAT) required for the conversion of serotonin to N-acetylserotonin. Melatonin is released into capillaries and carried to peripheral organs to transmit information about the light/dark cycle and to the SCN to contribute to the entrainment of the 24-hour central clock to the light dark cycle. B. A simplified model of the biological clock. Two transcription factors, BMAL1 (brain and muscleARN-1-like) and CLOCK (circadian locomotor output cycles kaput) form a heterodimer which activates the transcription of the genes for two proteins, Per (Period) and Cry (Cryptochrome). Cry and Per, along with other proteins, form a repressor complex that translocates back into the nucleus, allowing the Per-Cry complex to shut off the transcription of these genes in a negative feedback loop, creating the oscillator.
Fig2. Pathway of melatonin biosynthesis. The modifications of tryptophan that take place in melatonin biosynthesis in the pinealocyte are shown. The step that is regulated by the dark–light cycle is the conversion of serotonin to N-acetyl serotonin, catalyzed by arylakylamine-N-acetyl transferase.
The adrenal cortex is also a physiologically significant example of peripheral oscillators and their central control, because of the high amplitude change in the secretion of glucocorticoids and their broad influence on gene expression, including those of the peripheral oscillators, in target cells. Although the adrenal oscillator will lose its synchrony if the SCN is abolished and it is also under strong influence from the hypothalamic pituitary-adrenal axis as well as neural innervation, there is clear evidence for additional controls on its rhythm. In diurnal species, including humans and nonhuman primates, glucocorticoid levels are low shortly after the onset of darkness and begin to rise after the middle of the night when melatonin levels are falling. This timing is consistent with the inhibitory effects of melatonin, acting through the MT1 receptor, on glucocorticoid production and of its response to ACTH from the pituitary gland observed in monkeys and humans. The observation of direct inhibition of clock genes by melatonin in adrenal explants from monkeys strongly suggests a role for melatonin in the regulation of this important peripheral oscillator and, by extension, the rhythms of other tissues which are influenced by glucocorticoids.
