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Cell Biology International (2010) 34, 1199–1204 (Printed in Great Britain)
Review article
Melatonin as the most effective organizer of the rhythm of protein synthesis in hepatocytes in vitro and in vivo
Vsevolod Y Brodsky1 and Natalia D Zvezdina
Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov street, 119334 Moscow, Russia


Recent data has extended a large array of melatonin functions by the discovery of melatonin's involvement in the organization and regulation of the rhythm of intracellular protein synthesis. An ultradian rhythm in total protein synthesis has been detected in primary hepatocyte cultures 5 min after addition of 1–5 nM melatonin to the medium. The melatonin effect was mediated via its receptors (as shown in experiments with luzindole), leading to the cell synchronization as well as the mean rate of protein synthesis rate being increased. The chain of processes synchronizing the oscillation of the rate protein synthesis throughout the hepatocyte population includes Ca2+ fluxes {experiments with BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (acetomethyl ester)]}. Inhibition of protein kinase activity (experiments with H7) inhibited the synchronizing function of melatonin. Activation of protein kinase activity results in a shift of the protein synthesis oscillation; the effect was the same as melatonin added to the culture medium. In another series of experiments, after melatonin was intraperitoneally injected to rat (0.015–0.020 μg/kg), hepatocytes were isolated and cultures established. A synchronizing effect of melatonin in vivo was detected as early as in the estimates from the direct action of melatonin on cell cultures. In the cultures obtained from old rats provided with melatonin, the amplitude of protein synthesis rhythm was enhanced, i.e. cell–cell interactions were increased, as well as rate of the protein synthesis being enhanced.


Key words: aging, cell–cell interaction, hepatocyte, melatonin, protein synthesis rhythm, signal factor, ultradian rhythm

Abbreviations: BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (acetomethyl ester), PPPP, d-l-threo-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol-HCL

1To whom correspondence should be addressed (email brodsky.idb@bk.ru).

Part of a series marking the 70th birthday of the Cell Biology International Editor-in-Chief Denys Wheatley


1. Introduction

A rise and fall in the rate of protein synthesis is one of the ultradian (circahoralian) intracellular rhythms observed in many mammalian tissues in vivo and in vitro, as well as in invertebrates and bacteria (Brodsky, 1975, 2006; Lloyd and Rossi, 1992, 2008). Gangliosides, catecholamines and serotonin seem to be natural synchronizers of protein synthesis oscillations (Brodsky et al., 2000, 2003a, 2003b, 2004, 2005, 2007; Zvezdina et al., 2008). All these factors are calcium ions agonists and, accordingly, protein kinase activators. We now described the addition of melatonin to this set of synchronizers of the rhythm of protein synthesis.

2. The main functions of melatonin

Melatonin, first identified 50 years ago (Lerner et al., 1958), is the acetylated and methylated derivative of serotonin that ubiquitously occurs in cells (Vanecek, 1998; Tan et al., 2002, 2007). Enzymes of melatonin synthesis are activated by noradrenaline. Activity of these enzymes is inhibited by the blocking of beta-receptors (Kim and Klein, 2005). Melatonin is the most effective organizer of protein synthesis rhythm studied to date (see below). Unlike serotonin, melatonin permeates cell membranes as well as the haematoencephalic barrier. It acts as a potent antioxidant, cytoskeleton organizer, calmodulin antagonist, protein kinase C activator, a metal chelator, as well as a modulator of immune systems and some biorhythms (Reiter, 1998; Karbownik and Reiter, 2000; Kvetnoy et al., 2002; Reiter et al., 2002; Sato-Vega et al., 2004; Anisimov et al., 2006; Benitez-King, 2006; Tan et al., 2007). Melatonin also exerts a favourable effect on the heart, gastrointestinal tract and brain diseases. There is an association with some other disorders and with the sleeping state (see also Mishima et al., 1999; Arendt, 2003; Karasek, 2004; Reiter et al., 2004; Poeggeler, 2005; Martin et al., 2006; Maharay et al., 2007).

3. Melatonin as a synchronizer of protein synthesis oscillation: in vitro studies

In our first series of experiments (Brodsky, 2008, 2009, 2010a), primary cultures of rat hepatocytes on slides in serum-free medium were studied. Hepatocytes of adult rat are mature and represent a largely non-proliferating cell population. Protein synthesis rate was calculated by 3H-leucine incorporation into proteins corrected by reference to the free 3H-leucine pool (Brodsky et al., 1992, 2000). Both sparse and dense hepatocyte cultures were studied. In sparse cultures, consisting of widely separated cells, oscillation of the rate of protein synthesis could not be detected in fresh medium. In dense cultures with closely arranged cells obtained from the same cell suspension, protein synthesis rhythm was detected soon after renewal of culture medium, i.e. the cultures are capable of fast self-synchronization.

An extremely low dose of melatonin affected the organization of the synthesis rhythm in sparse (naturally asynchronous) cultures of hepatocytes. The rhythm was detected after 5 min exposure to 1, 2, 5, 50 and 200 nM melatonin (1 nM = 0.23×10−3 μg/ml); 0.5 nM was ineffective. The effective doses of melatonin are thus at least two orders of magnitude lower than for other signal factors, for example, phenylephrine 2 μM, serotonin 5 μM and noradrenalin 10 μM.

How does melatonin synchronizing occur? There are two possibilities. As noted above, melatonin permeates cell membranes and can act directly on chemical reactions, for example, as a free radical scavenger. Another mode of its action is via its receptors (Dubocovich et al., 1997; Vanecek, 1998; Sjoblom et al., 2003; Gordin et al., 2004; Radio et al., 2006). For example, this is the mechanism of melatonin action on cytoskeleton organization in which calcium and protein kinase C involvement is evident (Benitez-King, 2000, 2006; Tepperman et al., 2005).

In the case of synchronization of the protein synthetic rhythm, our work implies the participation of receptors. Luzindole is a specific antagonist of melatonin receptors (Vanecek, 1998; Sjoblom et al., 2003). When 2 or 5 nM melatonin was added to the culture medium of sparse hepatocyte cultures for 5 min together with 20 nM luzindole, the synchronizing action of melatonin was inhibited, and no rhythm was detected. In control cultures given melatonin but no luzindole, rhythm was apparent.

The action of melatonin via its receptors suggests that a chain processes results in the coordination of oscillations in protein synthesis. Bearing in mind some of the other synchronizers that have been studied (Brodsky et al., 2003, 2007), the implication is that Ca+2 and thereby calcium-dependent protein kinases may be responsible. An intracellular Ca+2 chelator, BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (acetomethyl ester) that abrogates calcium changes in the cytoplasm inhibited the synchronizing function of melatonin.

Protein kinase activity is another possible candidate in the cascade of events. Inhibition of protein kinase activity, mainly protein kinase C by H7 [1-(5-isoquinolinesulfonyl)-5-methylpiperasine dihydrochloride], prevented the synchronizing effect of melatonin (Brodsky et al., 2009). Stimulation of protein kinase C activity by melatonin has been described (Anton-Tay et al., 1999; Benitez-King, 2000, 2006; Sato-Vega et al., 2004; Tepperman at al, 2005; Sampson et al., 2006; Martin et al., 2006). The influence of melatonin on the Ca2+ fluxes might also be due to inhibition of calmodulin (Sato-Vega et al., 2004).

The crucial experiment was performed by adding 2 nM melatonin to the culture medium of dense cultures, which shifts the synthetic rhythm out of a phase (Brodsky et al., 2010a). Thus, the chain of processes resulting in the onset of the rhythm from chaotic oscillations may be presented as follows: signal factor (melatonin) → elevation of Ca+2 content in the cell cytoplasm → stimulation of protein kinase (mainly protein kinase C) activity → protein phosphorylation → shifts in individual cell rhythms and coordination accordingly of protein synthesis oscillations throughout cell population → common rhythm throughout the cell population.

Synchronizing function can be achieved independently by different signal factors (Zvezdina et al., 2008). For a ganglioside blockade, PPPP (d-l-threo-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol-HCl), a specific inhibitor of glucosyl-ceramide synthase that is the key enzyme of ganglioside synthesis (Li et al., 1993; Olshevski and Ladisch, 1998; Wen Deng et al., 2000), was used. One micromolar PPPP for 1 day diminished ganglioside content in the conditioned culture medium by >90%. Inhibition of ganglioside synthesis and shedding resulted in the loss of rhythm in dense spontaneously synchronous cultures (Brodsky et al., 2003a). Addition of 2 μM phenyleprine for 2 min to the medium of ganglioside-blocked cultures restored the rhythm. Blocking alpha-adrenoreceptors inhibited the synchronizing function of phenylephrine and resulted in the loss of protein synthetic rhythm. Addition of gangliosides to the medium restored the rhythm.

The key processes in protein synthesis synchronization are not, however, exclusively receptor-dependent, but result from calcium and protein kinase changes themselves. Non-receptor stimulation of Ca2+ elevation by 10 μM 2,5-di(tert-butyl)-1,4-benzohydroquinone (Khodorova and Astashkin, 1994) for 2 min (see Brodsky et al., 2003b) stimulated synchronization in sparse cultures. According to later data (Brodsky et al., 2007), inhibition of protein kinase activity prevented the synchronizing action of the signal factors that had been studied.

Protein phosphorylation can be a crucial factor in the organization of some ultradian rhythms (enzyme activity, protein content, etc.) has been shown by the Gilbert and Hammond group (Ferreira et al., 1994; Calvert-Evers and Hammond, 2000; Bhoola and Hammond, 2000). In other work, melatonin activated protein kinase C activity and influences the organization of the cytoskeleton by the phosphorylation of proteins (Benitez-King, 2000, 2006; Tepperman et al., 2005).

4. Melatonin as a synchronizer of protein synthesis oscillation: injection into rats

The second series of our experiments concerning the melatonin effects were more similar to the methods used in clinical practice, with melatonin being injected into rats (Brodsky et al., 2010b). Hepatocytes were isolated after 100 min injection of 0.015–0.020 μg/kg i.p. to either adult or old rats, and the cell cultures prepared. Changes in protein synthesis kinetics could be detected 1–2 days later.

The initial effect of injection by itself was studied. Intraperitoneal injection of NaCl solution did not synchronize sparse cultures, with no rhythm in protein synthesis being detected. The injection did not change the amplitude of the rhythm in cells of dense cultures from old rats.

The main result of the second series of experiments concerns the detection of protein synthesis rhythm in sparse (naturally asynchronous) cultures obtained from rats provided with melatonin 1 day earlier. This suggests that melatonin had accumulated in liver after intraperitoneal injection and synchronized protein synthesis oscillations in hepatocytes in vivo; the consequences of this are evident in the cell cultures a day later (Figure 1). The same conclusion was reached concerning the dense cultures obtained from cells of old rats; protein synthetic rhythm was used as a marker of the cell-to-cell cooperation due to intercellular interactions resulting in synchronization throughout the cell population.

The very existence of any rhythm in cell cultures indicates synchronization of the cells. The greater the amplitude of oscillation, the more intercellular cooperation will result in cell synchronization. If individual oscillations are not synchronous, the overall kinetics will be linear. Thus, the value of the amplitude defines the extent of expression of cell-to-cell cooperation in the formation of the overall (total) rhythm throughout the cell population. In control cultures, i.e. without melatonin (see above), the rhythm of protein synthesis seen in cells of old rats have a low amplitude, probably because cell–cell interactions in old animals are weak (Brodsky et al., 2004). After injection of melatonin into an old rat, the amplitude of the protein synthesis rhythm almost doubled, i.e. it achieved the level seen in younger animals. Another effect of melatonin on the cells of old rats concerns the mean level of the rate of protein synthesis. Unlike other synchronizers, the in vitro and in vivo action of melatonin essentially enhances the rate of protein synthesis that normally decreases with an animal's age. Both effects were retained for at least 2 days after injection of melatonin to old rats (Brodsky et al., 2010b). Thus, melatonin acts as a trigger to start a chain of processes that results in coordination of protein synthesis oscillations.

An intercellular mechanism of in vivo organization of protein synthesis rhythm was deduced from our previous data on the rhythm in slices of denervated liver. In this case, only direct cell–cell interactions can synchronize the protein synthesis oscillations. The in vivo trophic system, i.e. blood contains all the signal factors needed for synchronization of the protein synthesis oscillations (gangliosides, noradrenaline – a pharmacological analog of which is phenylephrine, serotonin and melatonin), and the level of these factors decreases on aging (Prozorovskaya, 1983; Nakamura et al., 1988; Senn et al., 1989; Harpin et al., 1990; Bergelson, 1995; Ozkok et al., 1999; Karasek, 2004). Thus, synchronous or asynchronous behaviour of a cell population, or even of different populations of a given organ, could depend on the composition of the blood serum in various normal or pathological conditions. We found that addition of gangliosides to the blood serum of old rats enhanced the amplitude of protein synthesis rhythm to the level of young rats. Therefore, the desirable functions of melatonin on elderly subjects are clear: this is evident both with cells and with aged patients. Some interesting studies have been reported on liver (Reiter et al., 2002; Yamomoto et al., 2003; Maharay et al., 2007; Catala et al., 2007; Molpeceres, 2007). In this regard, the antioxidant action of melatonin deserves particular attention; melatonin acts as an antioxidant enhancing the action of enzymes of the antioxidant system, including glutathione reductase, superoxide dismutase, nitric oxide synthase and glucose-6-phosphate dehydrogenase (Karbownik and Reiter, 2000; Maharay et al., 2007).

Again, it can be noted that extremely low doses of melatonin are needed for the regulation of a cell function, such as synchronization of the protein synthesis rhythm in vivo. The rhythm of protein synthesis is synchronized by a single injection of 0.015–0.020 μg/kg melatonin. For comparison, 1 or 3 mg of melatonin, i.e. 0.03–0.05 mg/kg human weight has several uses in human clinics or for sleep normalization.

The main results concerning the involvement of melatonin in the organization of protein synthesis rhythm can be presented as shown in Figure 2.

5. Conclusions

Recent data have shown a novel function of melatonin in its active involvement in the organization, i.e. the synchronization of the rhythm of protein kinetics based on total synthesis in hepatocyte cell population. The data extends a large set of known functions of melatonin, some of which are presented below:

Modulator of pigment cells

Free radical scavenger

Antagonist of calmodulin

Activator of protein kinase C

Modulator of immune system

Chelator of metals

Organizer of cytoskeleton

Modulator of certain biorhythms

Promoter of cell viability

Organizer of protein synthesis rhythm

The temporal organization of protein synthesis seems to be modest against the background of other melatonin functions. But protein synthesis is one of the most important functions of liver as long as the blood plasma proteins as well as specific enzymes of detoxication are among the main components of mammalian metabolism. Thus, temporal organization of this function modulated by melatonin is essential for the whole organism. The signal function of melatonin can be important for other mammalian organs besides liver. Recently, the same calcium–protein kinase mechanism of melatonin action on the organization of the rhythm of protein synthesis has been estimated for keratinocytes (Brodsky et al., 2010). Existing data concerning serotonin effects on different events of development (Pronina et al., 2003; Voronezhskaya et al., 2004; Mirochnik et al., 2005) add another interesting perspective to studies of melatonin. What is this developmental factor; is it serotonin as such or melatonin originating from serotonin? Recently, the effect of melatonin on the rate of the mouse blastocyst formation in vitro has been shown (Tian et al., 2010).

The organization of the rhythm protein synthesis may be of significance because of the ubiquitous occurrence of melatonin – from plants, bacteria and protists to all mammalian tissues. Being one of the prime signal systems of protein metabolism and organization of cell populations, melatonin, as well as its precursor serotonin, along with noradrenalin and dopamine, is conserved in a wide range of organisms and may be an important factor in multicellular evolution (see also Brodsky and Lloyd, 2008). The fractal nature of the rhythm of protein synthesis along with other ultradian oscillations with a set of functionally dependent periods may underlie tissue adaptations as an expression of the coordinated activity of cell populations (Lloyd and Rossi, 1992; Brodsky, 2006).

Although melatonin can easily permeate cell membrane, its action on the organization of protein synthesis kinetics is exerted via its receptors. The same concerns other functions of melatonin; the receptor-dependent action of melatonin was detected for survival, growth factor secretion and differentiation of bone marrow mesenchymal stem cells (Radio et al., 2006; Mias et al., 2008). Melatonin promotes differentiation of preosteoblast cell lines; luzindole, a competitive inhibitor of the binding of melatonin to transmembrane receptors, reduces the effect of melatonin (Roth et al., 1999). Melatonin via its receptor can also promote the viability and differentiation of neural stem cells (Xiangying Kong et al., 2008), as also the survival of new born neurons (Ramirez-Rodriguez et al., 2009).

Identification of intracellular pathway of the melatonin-receptor action on cell viability and differentiation is one of the goals of further studies. Is it the calcium–protein kinase pathway as detected in the organization of protein synthesis kinetics in hepatocytes and keratinocytes (Figure 3)? Separate data concerning activation of protein kinase C in some cells by melatonin support the possibility.

The action of melatonin is exerted via its receptors and initiates a chain of processes comprising calcium and protein kinases (Figure 3). Organization of the rhythm of protein synthesis by melatonin has been demonstrated both in vitro and in vivo systems and at nanomolar doses. Enhancement of amplitude of protein synthesis rhythm, i.e. expression of cell–cell communication in old animals has also been shown along with increase of the total protein synthesis rate. These newly discovered properties of melatonin are worthy of further attention, bearing in mind its influence on a number of diseases and on sleep states in humans.

Acknowledgements

Our experimental studies are supported by the grants from the Russian Fund for Basic Research. We are grateful to Dr. David Lloyd and Dr. Arsen S. Mikaelyan for valuable comments.

REFERENCES

Anisimov, VN, Popovich, IG, Zaberzhinski, MA, Anisimov, SV, Vesnushkin, GM and Vinogradova, IA (2006) Melatonin as antioxidant, genoprotector and anticarcinogen. Biochim Biophys Acta 1757, 573-89
Crossref   Medline   1st Citation  

Anton-Tay, F, Ramirez, G, Martinez, I and Benitez-King, G (1999) In vitro stimulation of protein kinase C by melatonin. Neurochem Res 23, 601-6
1st Citation  

Arendt, J (2003) Importance and relevance of melatonin to human biological rhythms. J Neuroendocrinol 15, 427-31
Crossref   Medline   1st Citation  

Benitez-King, G (2006) Melatonin as a cytoskeletal modulator: implications for cell physiology and disease. J Pineal Res 40, 1-9
Crossref   Medline   1st Citation   2nd   3rd   4th  

Benitez-King, G (2000) PKC activation by melatonin modulates vimentin intermediate filament organization in NIE-115 cells. J Pineal Res 29, 8-14
Crossref   Medline   1st Citation   2nd   3rd  

Bergelson, LD (1995) Serum gangliosides as endogenous immunomodulators. Immunology Today 16, 483-6
Crossref   Medline   1st Citation  

Bhoola, R and Hammond, K (2000) Modulation of the rhythmic patterns of expression of phosphoprotein phosphatases in human leukaemia cells. Cell Biol Int 24, 539-47
Crossref   Medline   1st Citation  

Brodsky, VY (1975) Protein synthesis rhythm. J Theor Biol 55, 167-200
Crossref   Medline   1st Citation  

Brodsky, VY (2006) Direct cell–cell communication. A new approach derived from recent data on the nature and self-organization of ultradian (circahoralian) intracellular rhythms. Biol Rev Cambridge Phylosoph Soc 82, 143-62
1st Citation   2nd  

Brodsky, VY and Lloyd, D (2008) Self-organized intracellular ultradian rhythms provide direct cell–cell communication. In Ultradian rhythms from molecules to mind (Lloyd D and Rossi, E L, eds), pp. 85-105, London, Springer
1st Citation  

Brodsky, VY, Boikov, PY, Nechaeva, NV, Yurovitsky, YG, Novikova, TE, Fateeva, VI and Shevchenko, NA (1992) The rhythm of protein synthesis does not depend on oscillations of ATP level. J Cell Science 103, 363-70
Medline   1st Citation  

Brodsky, VY, Nechaeva, NV, Zvezdina, ND, Prokazova, NV, Golovanova, NK, Novikova, TE, Gvasava, IG and Fateeva, VI (2000) Gangliodide-mediated synchronization of the protein synthesis activity in cultured hepatocytes. Cell Biol Int 24, 211-22
Crossref   Medline   1st Citation   2nd  

Brodsky, VY, Zvezdina, ND, Nechaeva, NV, Novikova, TE, Gvasava, IG, Fateeva, VI and Gracheva, HV (2003a) Loss of hepatocyte co-operative activity after inhibition of ganglioside GM1 synthesis and shedding. Cell Biol Int 27, 935-42
Crossref   Medline   1st Citation   2nd  

Brodsky, VY, Zvezdina, ND, Nechaeva, NV, Avdonin, PV, Novikova, TE, Gvasava, IG, Fateeva, VI and Malchenko, LA (2003b) Calcium ions as a factor of cell–cell cooperation in hepatocyte cultures. Cell Biol Int 27, 965-76
Crossref   Medline   1st Citation   2nd  

Brodsky, VY, Nechaeva, NV, Zvezdina, ND, Novikova, TE, Gvasava, IG, Fateeva, VI and Malchenko, LA (2004) Small cooperative activity of old rat's hepatocytes may depend on composition of the intercellular medium. Cell Biol Int 28, 311-6
Crossref   Medline   1st Citation   2nd  

Brodsky, VY, Zvezdina, ND, Nechaeva, NV, Novikova, TE, Gvasava, IG, Fateeva, VI and Malchenko, LA (2005) Single short-term signal that enhances cooperative activity of the old rat hepatocytes acts for several days. Cell Biol Int 29, 971-75
Crossref   Medline   1st Citation  

Brodsky, VY, Zvezdina, ND, Fateeva, VI and Malchenko, LA (2007) Involvement of protein kinases in self-organization of the protein synthesis rhythm by direct cell–cell communication. Cell Biol Int 31, 65-73
Crossref   Medline   1st Citation   2nd   3rd   4th  

Brodsky, VY, Golichenkov, VA, Zvezdina, ND, Dubovaya, TK, Fateeva, VI, Malchenko, LA, Burlakova, OV and Bespjatykh, AJ (2008) Melatonin enhances protein synthesis and synchronizes the synthesis rhythm in hepatocyte cultures of old rats. Ontogenez 39, (6), 443-47 (in Russian)
Medline   1st Citation   2nd  

Brodsky, VY, Golichenkov, VA, Zvezdina, ND, Fateeva, VI and Malchenko, LA Melatonin synchronizes protein synthesis rhythm as agonist of intracellular calcium and proteinkinases. Ontogenez 40, (3), 231-36 (in Russian)
1st Citation   2nd  

Brodsky, VY, Zvezdina, ND, Dubovaya, TK, Fateeva, VI and Malchenko, LA (2010a) Melatonin modulates protein synthesis rhythm. Bulletin Exp Biol Med in press
1st Citation   2nd  

Brodsky, VY, Zvezdina, ND, Dubovaya, TK, Fateeva, VI and Malchenko, LA (2010b) Melatonin injected intraperitoneally to rat synchronizes protein synthesis rhythm in primary hepatocyte cultures. Ontogenez in press
1st Citation   2nd  

Brodsky, VY, Terskikh, VV, Vasiliev, AV, Zvezdina, ND, Voroteljak, EA, Fateeva, VI and Malchenko, LA (2010) Self-organization of protein synthesis rhythm in HaCat cultures of human keratinocytes. Ontogenez in press
1st Citation  

Calvert-Evers, JL and Hammond, KD (2000) Temporal variations in protein tyrosine phosphatase activity during cell proliferation and differentiation. Cell Biol Int 24, 559-67
Crossref   Medline   1st Citation  

Catala, A, Zvara, A, Puskas, LG and Kitaika, K (2007) Melatonin-induced gene expression changes and its preventive effects on adriamycin-induced lipid peroxydation in rat liver. J Pineal Res 42, 43-9
Crossref   Medline   1st Citation  

Dubocovich, ML, Masana, S, Iacob, S and Sauri, DM (1997) Melatonin receptor antagonists that differentiate between human Mel (1a) and Mel (1b) recombinant subtypes. Arch Pharmacol 355, 365-75
Crossref   1st Citation  

Ferreira, GMH, Hammond, KD and Gilbert, DA (1994) Insulin stimulation of high frequency phosphorylation dynamics in murine erythroleukemic cells. BioSystems 33, 31-43
Crossref   Medline   1st Citation  

Gordin, MJ, Masana, MI, Hudson, RL, Gillete, MU and Dobocovich, ML (2004) Melatonin desensitizes MT2 receptors in the rat suprachiasmatic nucleus. FASEB J 18, 1646-56
Crossref   Medline   1st Citation  

Harpin, ML, Boutry, JM, Hauw, JJ, Baumann, N, Jounes-Chennoufi, A and Yavin, E (1990) Fetal calf serum gangliosides. Cell Devel Biol 26, 217-9
Crossref   1st Citation  

Karasek, M (2004) Melatonin, human aging, and age-related diseases. Exper Gerontol 39, 1723-9
Crossref   1st Citation   2nd  

Karbownik, M and Reiter, RJ (2000) Antioxidative effects of melatonin in protection against cellulular damage caused by ionizing radiation. Proceed Soc Exp Biol Med 225, 9-22
Crossref   1st Citation   2nd  

Khodorova, AB and Astashkin, EI (1994) A dual effect of arachidonic acid on Ca2+ transport systems in lymphocytes. FEBS Lett 353, 167-70
Crossref   Medline   1st Citation  

Kim, JS and Klein, DC (2005) Methionine adenosyltransferase: adrenergic-cAMP mechanism regulates a daily rhythm of pineal expression. J Biol Chem 280, 677-84
Medline   1st Citation  

Kvetnoy, IM, Ingel, IE, Kvetnaya, TV, Malinovskaya, NK, Rapoport, SI, Raikhlin, NT, Trovimov, AV and Yuzakov, VV (2002) Gasrointestinal melatonin. Cellular identification and biological role. Neuroendocrinol Lett 23, 121-32
Medline   1st Citation  

Lerner, A, Case, J and Takahashi, J (1958) Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Amer Chem Soc 80, 2587-89
1st Citation  

Li, R, Gage, D and Ladisch, S (1993) Biosynthesis and shedding of murine lymphoma gangliosides. Biochim Biophys Acta 1170, 283-90
Medline   1st Citation  

Lloyd, D and Rossi, EL (1992) Ultradian rhythms in life processes p. 419, London, Springer
1st Citation   2nd  

Lloyd, D and Rossi, E L (2008) Ultradian rhythms from molecules to mind p. 450, London, Springer
1st Citation  

Maharay, DS, Glass, BD and Daya, S (2007) Melatonin: new places in therapy. Biosci Rep 27, 299-320
Crossref   Medline   1st Citation   2nd   3rd  

Martin, V, Herrera, F and Carrera-Gonzalez, P (2006) Intracellular signaling pathways involved in cell growth inhibition of glioma cells by melatonin. Cancer Res 66, 1081-88
Crossref   Medline   1st Citation   2nd  

Mias, C, Trouche, E, Seguelas, MH, Calcagno, F, Dignat-George, F, Sabatier, F, Piercecchi-Marti, MD, Daniel, L, Bianchi, P and Calise, D (2008) Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney. Stem Cells 26, 1749-57
Crossref   Medline   1st Citation  

Mirochnik, V, Bosler, O, Calas, A and Ugrumov, M (2005) Long-lasting effects of serotonin deficiency on differentiating peptidergic neurons in the rat suprachiasmatic nucleus. Int J Develop Neurosci 23, 85-91
Crossref   1st Citation  

Mishima, K, Tozawa, T, Satoh, K, Matsumoto, Y, Hishikawa, Y and Okawa, k (1999) Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimers's type with disturbed sleep–waking. Biol Psychiatry 45, 417-21
Crossref   Medline   1st Citation  

Molpeceres, V, Mauriz, JL and Mediavilla, G (2007) Melatonin is able to reduce the apoptotic liver changes inducing by aging via inhibition of the intrinsic pathway of apoptosis. J Gerontol Sci. Series A 62, 687-95
1st Citation  

Nakamura, Y, Hishimoto, Y, Yamakawa, T and Suzuki, A (1988) Age-dependent changes in GM1 and GD1a expression in mouse liver. J Biochem 103, 396-98
Medline   1st Citation  

Olshevski, R and Ladisch, S (1998) Synthesis, shedding, and intracellular transfer of human medulloblastoma gangliosides: abrogation by a new inhibitor of glycosylceramide synthase. J Neurochem 70, 467-72
Crossref   Medline   1st Citation  

Ozkok, E, Cendiz, S and Guevener, B (1999) Age-dependent changes in liver ganglioside levels. J Basic Clinic Physiol Pharmacol 10, 337-44
1st Citation  

Poeggeler, B (2005) Melatonin, aging and age-related diseases. Endocrine 27, 201-12
Crossref   Medline   1st Citation  

Pronina, T, Adamskaya, E, Ugrumov, M, Kuznetsova, T, Shishkina, I, Babichev, V, Calas, A, Tramu, G, Mailly, P and Makarenko, I (2003) Influence of serotonin on the development and migration of gonadotropin-releasing hormone neurons in rat fetuses. J Neuroendocrinol 15, 549-58
Crossref   Medline   1st Citation  

Prozorovskaya, MP (1983) Age-related changes of adrenaline and noradrenaline in tissues of rats. Physiologichesky Journal SSSR 69, 1244-46 (In Russian)
1st Citation  

Radio, NM, Doctor, JC and Witt-Enderbi, PA (2006) Melatonin enhances alkaline phosphatase activity in differentiating human adult stem cells grown in osteogenic medium via melatonin receptors and MEK/ERK signaling cascade. J Pineal Res 40, 332-42
Crossref   Medline   1st Citation   2nd  

Ramirez-Rodriguez, G, Klempin, F, Babu, H, Benitez-King, G and Kempermann, G (2009) Melatonin modulates cell survival of new neurons in the hippocampus of adult mice. Neuropsychpharmacology 34, 2180-91
Crossref   1st Citation  

Reiter, RJ (1998) Melatonin, active oxygen species and neurological damage. Drug News Perspect 11, 291-6
Crossref   Medline   1st Citation  

Reiter, RJ, Tan, DX, Mayo, JC, Sainz, RM and Lopez-Burillo, S (2002) Melatonin longevity and health in the aged: an assessment. Free Radicals Res 36, 1323-9
Crossref   1st Citation   2nd  

Reiter, RJ, Tan, DX and Pappola, MA (2004) Melatonin relieves the neural oxidative burden that contributes to dementias. Ann NY Acad Sci 1035, 179-94
Crossref   Medline   1st Citation  

Roth, JA, Kim, B-G, Lin, WL and Cho, M (1999) Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem 274, 22041-7
Crossref   Medline   1st Citation  

Sampson, SR, Lupowitz, Z, Braiman, L and Zisapel, N (2006) Role of protein kinase C-alpha in melatonin signal transduction. Mol Cell Endocrinol 252, 82-7
Crossref   Medline   1st Citation  

Sato-Vega, E, Meza, I, Ramirez-Rodriges, G and Benitez-King, G (2004) Melatonin stimulates calmodulin phosphorylation by protein kinase C. J Pineal Res 37, 98-106
Crossref   Medline   1st Citation   2nd   3rd  

Senn, HJ, Orth, M, Fitzke, E, Wieland, H and Gerok, W (1989) Gangliosides in normal human serum. Concentrations, pattern and transport by lipoproteins. Europ J Biochem 181, 657-62
Crossref   Medline   1st Citation  

Sjoblom, M, Safsten, B and Flemstrom, G (2003) Melatonin induced signaling in clusters of human and rat duodenal enterocytes. Amer J Physiol 284, g1034-44
1st Citation   2nd  

Tan, D-X, Reiter, RJ and Manchester, LC (2002) Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radicals scavenger. Curr Topics Med Chem 2, 181-98
Crossref   1st Citation  

Tan, D-X, Manchester, LC, Terron, MP, Flores, Lj and Reiter, RJ (2007) One molecule, many derivatives: a never ending interaction of melatonin with reactive oxygen and nitrogen species. J Pineal Res 42, 28-42
Crossref   Medline   1st Citation   2nd  

Tepperman, BL, Soper, BD and Chang, Q (2005) Effect of protein kinase C on intracellular Ca+ signalling and integrity of intestinal epithelial cells. Eur J Pharmacol 45, 1-9
Crossref   1st Citation   2nd   3rd  

Tian, XZ, Wen, Q, Shi, JM, Liang-Wang, Zeng, SM, Tien, JH, Shu, SE and Liu, GS (2010) Effects of melatonin on in vitro development of mouse two-cell embryos cultured in HTF medium, Endocrin Res. 35, 17-23
Medline   1st Citation  

Vanecek, J (1998) Cellular mechanisms of melatonintion. Physiol Rev 78, 687-721
Medline   1st Citation   2nd   3rd  

Voronezhskaya, EE, Khabarova, MY and Nezlin, LP (2004) Apical sensory neurons mediate developmental retardation induced by conspecific environmental stimuli in freshwater pulmonate snails. Development 131, 3671-80
Crossref   Medline   1st Citation  

Deng, Wen, Li, R and Ladisch, S (2000) Influence of cellular ganglioside depletion on tumor formation. J Natl Cancer Inst 92, 912-7
Crossref   Medline   1st Citation  

Kong, Xiangying, Li, Xuekun, Cai, Zhe, Yang, Nan, Liu, Yanyong, Shu, Jun, Pan, Lin and Zuo, Pingring (2008) Melatonin regulates the viability and differentiation of rat midbrain neural stem cells. Cellular Molecular Neurobiol 28, 569-79
Crossref   1st Citation  

Yamomoto, H and Mohagan, PV (2003) In vivo and in vitro effects of melatonin or ganglioside GT1b on l-cysteine-induced brain mitochondrial DNA damage in mice. Toxicol Sci 73, 416-22
Crossref   Medline   1st Citation  

Zvezdina, ND, Malchenko, LA, Fateeva, VI and Brodsky, VY (2008) Signal factors of protein synthesis rhythm act independently in hepatocyte cultures. Ontogenez 39, (3), 198-207 (in Russian)
Medline   1st Citation  


Received 3 July 2010; accepted 26 July 2010

Published online 25 October 2010, doi:10.1042/CBI20100036


© The Author(s) Journal compilation © 2010 Portland Press Limited


ISSN Print: 1065-6995
ISSN Electronic: 1095-8355
Published by Portland Press Limited on behalf of the International Federation for Cell Biology (IFCB)