Prolonged exposure to melatonin leads to time-dependent sensitization of adenylate cyclase and down-regulates melatonin receptors in pars tuberalis cells from ovine pituitary.

Melatonin and somatostatin are known to exert similar effects on locomotor activity. We have previously demonstrated that acute melatonin treatment regulates somatostatin receptor function in the rat frontoparietal cortex. However, the effects of subchronic and chronic melatonin treatment on the somatostatin receptor-G protein-adenylyl cyclase system in the rat frontoparietal cortex are unknown. Melatonin was administered subcutaneously at a daily dose of 25 microg/kg for 4 days, 1 wk or 2 wk. Twenty-four hours after the last injection, the animals were sacrificed. Melatonin did not alter the somatostatin-like immunoreactivity content in the frontoparietal cortex from control and melatonin-treated rats during any of the previously indicated periods. Four days of melatonin administration induced both an increase in the number of [(125)I]-Tyr11-somatostatin receptors and a decrease in the affinity of somatostatin for its receptors in frontoparietal cortical membranes. The increased number of somatostatin receptors in the melatonin-treated rats was associated with an increased capacity of somatostatin to inhibit basal and forskolin-stimulated adenylyl cyclase activity. Melatonin administration for 4 days induced a higher adenylyl cyclase activity both under basal conditions and after direct stimulation of the enzyme with forskolin. No significant differences were observed in the function of Gi proteins in the 4-day melatonin-treated rats. Western blot analyses showed that the 4-day melatonin treatment reduced Gialpha(2) levels, without altering the amount of Gialpha(1). These melatonin-induced changes reverted to control values after 7 or 14 days of treatment. Altogether, the present findings suggest that subchronic melatonin treatment modulates the somatostatin receptor/effector system in the rat frontoparietal cortex.

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Effects of subchronic and chronic melatonin treatment on somatostatin binding and its effects on adenylyl cyclase activity in the rat frontoparietal cortex

Izquierdo-Claros¹,

Boyano‐Adánez²,

Arilla‐Ferreiro³

2002

“…The expressed receptor coupled to a Gi protein in the host cells suggesting that the cAMP signal transduction pathway is possibly the major effector for the anti‐proliferative effects of melatonin. Although it is well known that melatonin is able to cause auto‐ [42] and hetero‐ [43] desensitizing effects on biological responses, it is interesting to mention that melatonin did not cause auto desensitization of S‐91 cells expressing the MT‐1 receptor, even after prolonged exposures for 96 hr or at high concentrations used in our experiments.…”

Section: Discussionmentioning

confidence: 75%

MT‐1 melatonin receptor expression increases the antiproliferative effect of melatonin on S‐91 murine melanoma cells

Kadekaro

Andrade

Flöeter-Winter

et al. 2004

Melatonin, a derivative of tryptophan that is present in all vertebrates, was first described in bovine pineal gland. It is known that melatonin is a highly conserved molecule, present also in unicellular organisms and plants. Several effects of melatonin have been described, including receptor- and non-receptor-mediated actions. Herein, we studied the effects of melatonin on in vitro and in vivo cell proliferation of Cloudman S-91 murine melanoma cells. We demonstrated that melatonin treatment significantly inhibits S-91 melanoma cell proliferation in vitro (EC50 = 10-7 m) as well as reduces tumor growth in vivo. We also demonstrated that melatonin directly increases the activity of the antioxidant enzymes catalase and glutathione peroxidase. These effects are most likely triggered through the direct intracellular action of melatonin, since the presence of receptors could not be demonstrated in this cell line. Expression of MT-1 melatonin receptor by stable transfection, mediated a dramatic antiproliferative melatonin effect (EC50 = 10-10 m) in S-91 cells. The expressed receptor is negatively coupled to the adenylyl cyclase/cyclic AMP signaling pathway via Gi protein. These results suggest that expression of the MT-1 melatonin receptor in melanoma cells is a potential alternative approach to specifically target cells in cancer therapeutic treatment.

“…However, the overall amplitude of the pCREB rhythm in

{MT}_{1 / 2}^{- false/ -}

mice is significantly dampened as compared to WT animals. It is well known that melatonin acutely inhibits cAMP accumulation and CREB phosphorylation . As an additional effect, chronic melatonin exposure (>4 hours) leads to a time‐dependent sensitization of the adenylyl cyclase in pars tuberalis cells .…”

Section: Discussionmentioning

confidence: 99%

Melatonin modulates daytime‐dependent synaptic plasticity and learning efficiency

Jilg

Bechstein

Saade

et al. 2019

Mechanisms of hippocampus‐related memory formation are time‐of‐day‐dependent. While the circadian system and clock genes are related to timing of hippocampal mnemonic processes (acquisition, consolidation, and retrieval of long‐term memory [LTM]) and long‐term potentiation (LTP), little is known about temporal gating mechanisms. Here, the role of the neurohormone melatonin as a circadian time cue for hippocampal signaling and memory formation was investigated in C3H/He wildtype (WT) and melatonin receptor‐knockout (MT1/2-false/-) mice. Immunohistochemical and immunoblot analyses revealed the presence of melatonin receptors on mouse hippocampal neurons. Temporal patterns of time‐of‐day‐dependent clock gene protein levels were profoundly altered in MT1/2-false/- mice compared to WT animals. On the behavioral level, WT mice displayed better spatial learning efficiency during daytime as compared to nighttime. In contrast, high error scores were observed in MT1/2-false/- mice during both, daytime and nighttime acquisition. Day‐night difference in LTP, as observed in WT mice, was absent in MT1/2-false/- mice and in WT animals, in which the sympathetic innervation of the pineal gland was surgically removed to erase rhythmic melatonin synthesis. In addition, treatment of melatonin‐deficient C57BL/6 mice with melatonin at nighttime significantly improved their working memory performance at daytime. These results illustrate that melatonin shapes time‐of‐day‐dependent learning efficiency in parallel to consolidating expression patterns of clock genes in the mouse hippocampus. Our data suggest that melatonin imprints a time cue on mouse hippocampal signaling and gene expression to foster better learning during daytime.