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Melatonin stimulates dendrite formation and complexity in the hilar zone of the rat hippocampus: participation of the Ca++/Calmodulin complex.

Domínguez-Alonso A, Valdés-Tovar M, Solís-Chagoyán H, Benítez-King G - Int J Mol Sci (2015)

Bottom Line: We found that the CaMKII inhibitor, KN-62, abolished the MEL stimulatory effects on dendritogenesis and that MEL increased the relative amount of CaM in the soluble fraction of hippocampal slices.Our results indicate that MEL stimulates dendrite formation through CaMKII and the translocation of CaM to the soluble fraction.Data strongly suggest that MEL could repair the loss of hippocampal dendrites that occur in neuropsychiatric disorders by increasing CaM levels and activation of CaMKII.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Neurofarmacología, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco No. 101, Col. San Lorenzo-Huipulco, CP 14370 Tlalpan, DF, Mexico. aline.dmgzalonso@gmail.com.

ABSTRACT
Melatonin (MEL), the main product synthesized by the pineal gland, stimulates early and late stages of neurodevelopment in the adult brain. MEL increases dendrite length, thickness and complexity in the hilar and mossy neurons of hippocampus. Dendrite formation involves activation of Ca2+/Calmodulin (CaM)-dependent kinase II (CaMKII) by CaM. Previous work showed that MEL increased the synthesis and translocation of CaM, suggesting that MEL activates CaM-dependent enzymes by this pathway. In this work we investigated whether MEL stimulates dendrite formation by CaMKII activation in organotypic cultures from adult rat hippocampus. We found that the CaMKII inhibitor, KN-62, abolished the MEL stimulatory effects on dendritogenesis and that MEL increased the relative amount of CaM in the soluble fraction of hippocampal slices. Also, PKC inhibition abolished dendritogenesis, while luzindole, an antagonist of MEL receptors (MT1/2), partially blocked the effects of MEL. Moreover, autophosphorylation of CaMKII and PKC was increased in presence of MEL, as well as phosphorylation of ERK1/2. Our results indicate that MEL stimulates dendrite formation through CaMKII and the translocation of CaM to the soluble fraction. Dendritogenesis elicited by MEL also required PKC activation, and signaling through MT1/2 receptors was partially involved. Data strongly suggest that MEL could repair the loss of hippocampal dendrites that occur in neuropsychiatric disorders by increasing CaM levels and activation of CaMKII.

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Schematic drawing of the signaling pathway by which Melatonin stimulates dendrite formation. Melatonin (MEL) binds to membrane receptors (MT2/MT1) to activate PKC through the diacylglycerol (DAG) pathway. Also, the indoleamine can diffuse through the plasmatic membrane to directly interact with protein kinase C (PKC). This enzyme may phosphorylate calmodulin (CaM), which can bind to Ca2+/CaM Kinase II (CaMKII) with higher affinity. CaM-activated CaMKII undergoes autophosphorylation which induces its targeting to the cytoskeletal compartment where it binds and phosphorylates MAP2 to constitute dendrites. Also, PKC may increase CaM levels in the soluble fraction by an enhanced biosynthesis or by targeting from the cytoskeletal to the soluble compartment.
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ijms-16-01907-f009: Schematic drawing of the signaling pathway by which Melatonin stimulates dendrite formation. Melatonin (MEL) binds to membrane receptors (MT2/MT1) to activate PKC through the diacylglycerol (DAG) pathway. Also, the indoleamine can diffuse through the plasmatic membrane to directly interact with protein kinase C (PKC). This enzyme may phosphorylate calmodulin (CaM), which can bind to Ca2+/CaM Kinase II (CaMKII) with higher affinity. CaM-activated CaMKII undergoes autophosphorylation which induces its targeting to the cytoskeletal compartment where it binds and phosphorylates MAP2 to constitute dendrites. Also, PKC may increase CaM levels in the soluble fraction by an enhanced biosynthesis or by targeting from the cytoskeletal to the soluble compartment.

Mentions: In this paper we showed that both CaMKII and PKC participate in the mechanism by which MEL stimulates the three stages of dendritogenesis: dendrite formation, enlargement and complexity by two approaches: by pharmacological inhibition and by autophosphorylation. Our results also suggest that PKC acts upstream CaMKII and downstream to the MEL receptors and that ERK1/2 is involved in this signaling pathway. One important finding is that the CaM soluble pool is increased in hippocampal slices cultured with MEL indicating that CaM is available for CaMKII activation. Taken together, our data indicate that both receptor- and non-receptor-mediated signaling are concertedly involved in dendritogenesis triggered by MEL (Figure 9). More experiments are necessary for a more in-depth understanding of the mechanisms of CaM regulation exerted by MEL. Because dendrite formation is crucial for synaptogenesis, the results obtained in this study support that it is possible to stimulate neurodevelopment in the adult brain to reestablish the hippocampal synaptic connectivity lost in neuropsychiatric disorders.


Melatonin stimulates dendrite formation and complexity in the hilar zone of the rat hippocampus: participation of the Ca++/Calmodulin complex.

Domínguez-Alonso A, Valdés-Tovar M, Solís-Chagoyán H, Benítez-King G - Int J Mol Sci (2015)

Schematic drawing of the signaling pathway by which Melatonin stimulates dendrite formation. Melatonin (MEL) binds to membrane receptors (MT2/MT1) to activate PKC through the diacylglycerol (DAG) pathway. Also, the indoleamine can diffuse through the plasmatic membrane to directly interact with protein kinase C (PKC). This enzyme may phosphorylate calmodulin (CaM), which can bind to Ca2+/CaM Kinase II (CaMKII) with higher affinity. CaM-activated CaMKII undergoes autophosphorylation which induces its targeting to the cytoskeletal compartment where it binds and phosphorylates MAP2 to constitute dendrites. Also, PKC may increase CaM levels in the soluble fraction by an enhanced biosynthesis or by targeting from the cytoskeletal to the soluble compartment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307341&req=5

ijms-16-01907-f009: Schematic drawing of the signaling pathway by which Melatonin stimulates dendrite formation. Melatonin (MEL) binds to membrane receptors (MT2/MT1) to activate PKC through the diacylglycerol (DAG) pathway. Also, the indoleamine can diffuse through the plasmatic membrane to directly interact with protein kinase C (PKC). This enzyme may phosphorylate calmodulin (CaM), which can bind to Ca2+/CaM Kinase II (CaMKII) with higher affinity. CaM-activated CaMKII undergoes autophosphorylation which induces its targeting to the cytoskeletal compartment where it binds and phosphorylates MAP2 to constitute dendrites. Also, PKC may increase CaM levels in the soluble fraction by an enhanced biosynthesis or by targeting from the cytoskeletal to the soluble compartment.
Mentions: In this paper we showed that both CaMKII and PKC participate in the mechanism by which MEL stimulates the three stages of dendritogenesis: dendrite formation, enlargement and complexity by two approaches: by pharmacological inhibition and by autophosphorylation. Our results also suggest that PKC acts upstream CaMKII and downstream to the MEL receptors and that ERK1/2 is involved in this signaling pathway. One important finding is that the CaM soluble pool is increased in hippocampal slices cultured with MEL indicating that CaM is available for CaMKII activation. Taken together, our data indicate that both receptor- and non-receptor-mediated signaling are concertedly involved in dendritogenesis triggered by MEL (Figure 9). More experiments are necessary for a more in-depth understanding of the mechanisms of CaM regulation exerted by MEL. Because dendrite formation is crucial for synaptogenesis, the results obtained in this study support that it is possible to stimulate neurodevelopment in the adult brain to reestablish the hippocampal synaptic connectivity lost in neuropsychiatric disorders.

Bottom Line: We found that the CaMKII inhibitor, KN-62, abolished the MEL stimulatory effects on dendritogenesis and that MEL increased the relative amount of CaM in the soluble fraction of hippocampal slices.Our results indicate that MEL stimulates dendrite formation through CaMKII and the translocation of CaM to the soluble fraction.Data strongly suggest that MEL could repair the loss of hippocampal dendrites that occur in neuropsychiatric disorders by increasing CaM levels and activation of CaMKII.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Neurofarmacología, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco No. 101, Col. San Lorenzo-Huipulco, CP 14370 Tlalpan, DF, Mexico. aline.dmgzalonso@gmail.com.

ABSTRACT
Melatonin (MEL), the main product synthesized by the pineal gland, stimulates early and late stages of neurodevelopment in the adult brain. MEL increases dendrite length, thickness and complexity in the hilar and mossy neurons of hippocampus. Dendrite formation involves activation of Ca2+/Calmodulin (CaM)-dependent kinase II (CaMKII) by CaM. Previous work showed that MEL increased the synthesis and translocation of CaM, suggesting that MEL activates CaM-dependent enzymes by this pathway. In this work we investigated whether MEL stimulates dendrite formation by CaMKII activation in organotypic cultures from adult rat hippocampus. We found that the CaMKII inhibitor, KN-62, abolished the MEL stimulatory effects on dendritogenesis and that MEL increased the relative amount of CaM in the soluble fraction of hippocampal slices. Also, PKC inhibition abolished dendritogenesis, while luzindole, an antagonist of MEL receptors (MT1/2), partially blocked the effects of MEL. Moreover, autophosphorylation of CaMKII and PKC was increased in presence of MEL, as well as phosphorylation of ERK1/2. Our results indicate that MEL stimulates dendrite formation through CaMKII and the translocation of CaM to the soluble fraction. Dendritogenesis elicited by MEL also required PKC activation, and signaling through MT1/2 receptors was partially involved. Data strongly suggest that MEL could repair the loss of hippocampal dendrites that occur in neuropsychiatric disorders by increasing CaM levels and activation of CaMKII.

Show MeSH
Related in: MedlinePlus