1. Melatonin Secretion Patterns

 As shown in Figure 16-4, melatonin from the pineal gland sends two kinds of information to the rest of the body. The first is whether, during any given 24-hr period, it is dark or light outside. In the dark, synthesis and circulating levels of melatonin are high; when it is light, synthesis ceases and circulating levels are diminished. It is these changes in serum melatonin levels through which organs with melatonin receptors sense whether it is light or dark. In humans, the melatonin rhythm is absent at birth but is apparent at 6 months of age and the magnitude of the nocturnal secretion of melatonin peaks in early childhood. Throughout adult hood pineal size and hormone production continue to decrease with each decade of life (compare the different curves in Figure 1). In a given individual the pat tern of melatonin secretion is highly reproducible, with much greater variability seen between individuals than within one person over time. This interindividual variability is particularly notable with the amplitude of the melatonin peak during darkness.

Fig1. Patterns of melatonin secretion. A. The pineal conveys information about the light–dark cycle of the current day because melatonin is secreted only during darkness. Serum levels of melatonin rise several-fold to a peak in the midpoint of the dark cycle. Peak melatonin levels are seen during childhood and decrease progressively during adulthood and aging. B. The pineal gland also conveys seasonal information by varying with the length of days. As the areas under these two curves indicate, the shorter the day, the more melatonin is produced and the longer it is present in the bloodstream.

For human adults in temperate zones, melatonin levels begin to increase around 10:00 in the evening (shortly after dark), peak in the middle of the night, and decrease by 7:00 the next morning (in the morning light). As shown in part B of Figure 1, the pineal gland sends a second kind of information to the periphery concerning the length of light and dark periods, i.e., day length. Longer days will keep melatonin production and secretion suppressed and shorter days will lead to longer periods of exposure of peripheral organs to melatonin. These functions of melatonin are highly important in species which need such seasonal information to prepare for hibernation or reproductive functions that must be timed properly for optimally timed birth of the young. Some reports indicate that humans also respond to changes in day length with altered melatonin secretion, but, because these measurements are quite difficult to control for, this point has not yet been definitively established.

2. Regulation of Melatonin Synthesis

Figure 2A depicts in more detail the regulation of the synthesis of melatonin by the pinealocyte. The neurotransmitters that transmit the information from the melanopsin-containing ipRGCs in the inner layer of the retina do so through the secretion of the neurotransmitters PACAP (pituitary adenyl cyclase activating protein) and glutamate. When the light signal is positive, the SCN neuron secretes GABA (γ-amino butyric acid) which inhibits the firing of the neurons with which it synapses in the paraventricular nucleus of the hypothalamus. The signal to the pineal is interrupted and no melatonin is made. During darkness (no light signal) the SCN neuron secretes glutamate, an activating neuropeptide, and the PVN neuron transmits the signal along the pathway seen in Figure 3 and shown in more detail here.

Fig2. Regulation of melatonin synthesis. A. 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.

Fig3. Retinal-pineal neural connections. A. Light travels through the layer of retinal ganglion cells (RGC) and the neural cells in the inner retina to the rods and cones in the photoreceptor layer of the retina. The rods and cones send neural signals back through the inner retina to the ganglia, and through the optic nerve to the visual areas of the brain. A small number of the RGCs contain melanopsin and have intrinsic photoreceptor capability (ipRGC). These cells send neural signals to nonvisual (nonimage-forming) areas of the brain. Among these signals are those that eventually reach the pineal gland. B. The neural pathway that connects the melanopsin-containing RGC cells to the pineal gland is shown. The photic information from the retina is first sent to the suprachiasmatic nucleus (SCN), the location of the central biological clock (see Figure2). From there the signal travels to the paraventricular nucleus of the hypothalamus, the intermediolateral nucleus, and the superior cervical ganglion which transmits the signal to the pineal gland. The neurotransmitters involved in transmitting the signals in the pathway are detailed in Figure2. RPE, retinal pigment epithelium.

At the final connection between the axon of the neuron of the superior cervical ganglion and the pinealocyte, norepinephrine is secreted. NE interacts with its adenyl cyclase-coupled β-adrenergic receptors leading to activation of protein kinase A. PKA phosphorylates CREB (cyclic AMP response element binding protein; see Chapter 1), activating the transcription of the mRNA encoding the enzyme (AANAT) that converts serotonin to N-acetylserotonin, which is then methylated to form melatonin.

As shown in Figure4 regulation of AANAT activity is also accomplished by phosphorylation of specific serine residues of the enzyme protein molecule by PKA activated by the elevated levels of cyclic AMP in response to NE release during darkness. Phosphorylated AANAT forms a complex with a cytoplasmic protein, 14-3-3, in which the enzyme is more active and, most importantly, is protected from degradation by proteosomes. 14-3-3 proteins comprise a family that is able to bind to and thereby influence the activity and longevity of a variety of intracellular proteins. In the light, as NE and cyclic AMP levels fall, nonphosphorylated and noncomplexed AANAT is rapidly degraded and melatonin synthesis and secretion diminishes, then ceases. The relative contribution of transcriptional and posttranslational control of AANAT’s activity varies with species. In ungulates and primates, including humans, enzyme protein phosphorylation is the predominant if not the only mechanism of AANAT regulation.

Fig4. Posttranslational control of AANAT. Transcriptional control of AANAT (arylakylamine-N-acetyl transferase), the enzyme that catalyzes the rate-limiting step of melatonin production, was described in Figure 2A. A second, equally important, mechanism of posttranslational control is presented there. Cyclic AMP, stimulated by NE release, activates cAMP-dependent protein kinase (PKA). PKA phosphorylates specific sites on the AANAT molecule, increasing its affinity for a regulatory protein, 14-3-3. When bound to 14-3-3, AANAT is protected from degradation through proteolysis and catalyzes serotonin acetylation more efficiently. The activation of AANAT is rapidly reversed at the beginning of the light cycle when NE release from the SCG axon terminal ceases.

Melatonin is released into the vascular system from which it reaches the peripheral organs that have melatonin receptors. Some melatonin also circulates to the SCN where, along with glutamate and PACAP from the ipRGC, the central 24-hour clock is entrained to the light/dark cycle. Since melatonin is readily released into the bloodstream and not stored within the gland, the regulation of its secretion and serum levels lies entirely in the regulation of its production at the step of the acetylation of serotonin.

3. Circadian Rhythmicity of Melatonin Secretion

The circadian rhythmicity of the pineal gland is disrupted if the connection with the SCN is severed, emphasizing the SCN’s role as the generator of the melatonin rhythm, as well as some other circadian rhythms in the body. In the absence of light, the approximate 24-hour cycle of the SCN will keep melatonin synthesis on this schedule, but serum levels of the hormones will not continue to convey information about light and darkness. The basic operating mechanism of the central biological clock in the SCN is an interlinked set of positive and negative feedback loops in the transcription and translation of certain genes. One such loop is shown in Figure 16-5B. BMAL1 and CLOCK are positive transcription factors that bind to the E-box (Enhancer box) in the promoter region of the genes for, among other proteins, Per (period) and Cry (cryptochrome). In the presence of BMAL1 and CLOCK, the mRNA for these proteins increases and is translated in the cytoplasm. As the levels of the proteins in the cytoplasm increase, they, along with other cytoplasmic proteins, form a complex that translocates to the nucleus where Cry-Per represses transcription so that further synthesis of the genes is shut down. Per and Cry undergo protein degradation, lowering their levels, the repression is released, and the cycle begins again. Other regulatory loops interact with this one, stabilizing its rhythmicity. In addition, posttranslational modifications such as phosphorylation and acetylation of the positive and negative regulatory proteins also play roles in maintaining the rhythm of the SCN central clock.

اخر الاخبار

اخبار العتبة العباسية المقدسة

ملتقى الكوثر الثالث يشهد عرض مشهد حواري بعنوان شريك العمر أم شريك الفكر؟

إقامة مسابقة (مرفأ النور) العلمية للمشاركات في فعاليات ملتقى الكوثر بنسخته الثالثة

ضمن ملتقى الكوثر الثالث.. ورشة تسلط الضوء على بناء الوعي القرآني لدى النساء

شعبة فاطمة بنت أسد (عليها السلام): ملتقى الكوثر منصةً لتحقيق وعي أسري مستند للقرآن الكريم

المزيد

الآخبار الصحية

نظام غذائي شائع قد يؤدي إلى ارتفاع الكوليسترول الضار

تحذيرات هامة من عواقب تناول "أيبوبروفين" مع أدوية شائعة

علامات مبكرة للإيبولا يمكن الخلط بينها وبين الإنفلونزا

خبراء: الفيروسات مثل هانتا وإيبولا أصبحت أكثر شيوعا وفتكاً

المزيد

الآخبار التكنلوجية

الليلة.. هلال القمر يلتقي كوكبي الزهرة والمشتري

إيلون ماسك يخسر دعواه القضائية أمام أوبن إيه.آي

مهمة فضائية "أوروبية صينية" لكشف أسرار الرياح الشمسية

انتهاء رحلة "السفينة الموبوءة".. وهذا مصير من بقي على متنها

المزيد

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Effects of Estrogen on Bone

Uterine Effects of Estrogen and Progesterone

Menopause

Chemistry and Metabolism of Female Steroid Hormones: Feedback Effects on the Hypothalamus and Pituitary

Control of the Ovary by the Hypothalamus and Pituitary

Synthesis of Progesterone and Estrogens