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Research ArticleNeuropharmacology

Melatonin Receptors Trigger cAMP Production and Inhibit Chloride Movements in Nonpigmented Ciliary Epithelial Cells

Fernando Huete-Toral, Almudena Crooke, Alejandro Martínez-Águila and Jesús Pintor
Journal of Pharmacology and Experimental Therapeutics January 2015, 352 (1) 119-128; DOI: https://doi.org/10.1124/jpet.114.218263
Fernando Huete-Toral
Departamento de Bioquímica y Biología Molecular IV, Facultad de Óptica y Optometría, Universidad Complutense de Madrid, Madrid, Spain
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Almudena Crooke
Departamento de Bioquímica y Biología Molecular IV, Facultad de Óptica y Optometría, Universidad Complutense de Madrid, Madrid, Spain
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Alejandro Martínez-Águila
Departamento de Bioquímica y Biología Molecular IV, Facultad de Óptica y Optometría, Universidad Complutense de Madrid, Madrid, Spain
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Jesús Pintor
Departamento de Bioquímica y Biología Molecular IV, Facultad de Óptica y Optometría, Universidad Complutense de Madrid, Madrid, Spain
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Abstract

Melatonin and its analog 5-MCA-NAT (5-methylcarboxyamino-N-acetyl tryptamine) are active compounds reducing intraocular pressure (IOP). This action is mediated through MT2 and the putative MT3 melatonin receptor, producing a transient reduction of IOP that lasts for a few hours and has not yet been characterized. The use of melatonin and its analog are causing a decrease in chloride efflux from rabbit nonpigmented epithelial cells (NPE), possibly explaining the decrease in IOP. Melatonin and 5-MCA-NAT inhibited rabbit NPE chloride release in a concentration-dependent manner, whereas the pD2 values were between 4.5 ± 1.2 and 4.4 ± 1.0, respectively. Melatonin hypotensive action was enhanced by the presence of MT2 antagonists, such as DH97 (N-pentanoyl-2-benzyltryptamine) and 4-P-P-DOT (4-phenyl-2-propionamidotetralin) and by the nonselective melatonin receptor antagonist luzindole. Prazosin (1.5 µM) partially reverses the melatonin action by acting as a selective MT3 antagonist. However, at 15 nM it acts as an α-adrenergic receptor antagonist, enhancing the melatonin effect. Regarding the intracellular pathways triggered by melatonin receptors, neither phospholipase C/protein kinase C pathway nor the canonical reduction of intracellular cAMP was responsible for melatonin or 5-MCA-NAT actions. On the contrary, the application of these substances produced a concentration-dependent increase of cAMP, with pD2 values of 4.6 ± 0.2 and 4.9 ± 0.7 for melatonin and 5-MCA-NAT, respectively. In summary, melatonin reduces the release of chloride concomitantly to cAMP generation. The reduction of Cl− secretion accounts for a decrease in the water outflow and therefore a decrease in aqueous humor production. This could be one of the main mechanisms responsible for the reduction of IOP after application of melatonin and 5-MCA-NAT.

Footnotes

    • Received July 11, 2014.
    • Accepted October 23, 2014.
  • This work was supported by grants from the Spanish Ministry of Economy and Competition [Grants SAF2010-16024 and SAF-2013-44416-R]; and the Ministry of Health Social Services and Equality RETICS [Grant RD12/0034/0001]. Additionally, this work was supported by Spanish Ministry of Economy and Competition studentship to F.H.-T. and Universidad Complutense de Madrid studentships to A.M.-Á.

  • dx.doi.org/10.1124/jpet.114.218263.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 352 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 1
1 Jan 2015
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Research ArticleNeuropharmacology

Melatonin Reduces the Ciliary Release of Chloride via cAMP

Fernando Huete-Toral, Almudena Crooke, Alejandro Martínez-Águila and Jesús Pintor
Journal of Pharmacology and Experimental Therapeutics January 1, 2015, 352 (1) 119-128; DOI: https://doi.org/10.1124/jpet.114.218263

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Research ArticleNeuropharmacology

Melatonin Reduces the Ciliary Release of Chloride via cAMP

Fernando Huete-Toral, Almudena Crooke, Alejandro Martínez-Águila and Jesús Pintor
Journal of Pharmacology and Experimental Therapeutics January 1, 2015, 352 (1) 119-128; DOI: https://doi.org/10.1124/jpet.114.218263
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