Short-Term in Situ Action of Melatonin on Ion Transport in Mice Kept at Restraint Stress


  • University of Kerala, Department of Zoology, Thiruvananthapuram, Kerala, 695 581, India


Melatonin, a pleiotropic hormone, is involved in many physiological functions including combating oxidative stress. However, its role in ion transport during stress response is not yet understood. The dose-dependent effect of in situ melatonin was examined in Swiss albino mice. Perfusion of melatonin at 10-7 M for 20 minutes produced a significant decrease in Na+, K+-ATPase activity in the kidney, liver, stomach and intestinal tissues. A dose-responsive decrease in cytosolic and mitochondrial H+ ATPase activity was found in these tissues after melatonin perfusion. Likewise, the cytosolic and mitochondrial Ca2+ ATPase activities decreased in the kidney, liver, stomach and intestine. The mitochondrial Mg2+ ATPase activity decreased in the tested tissues in a dose-responsive manner. Subjecting mice to restraint stress for seven days increased the Na+, K+-ATPase, H+ ATPase, Ca2+ ATPase and Mg2+ ATPase activities to significant levels in kidney, liver, stomach and intestinal tissues. On the contrary, in-situ perfusion of melatonin to stressed mice at 10-9 M caused decrease in the stress-induced hyperactivity of these transmembrane ion transporters. These results provide evidence for a role of melatonin in ion transporter activity and point to a protective role of melatonin in ion transport during stress response in mice.


ATPase, Melatonin, Mice, Stress.

Subject Discipline

Pharmacy and Pharmacology

Full Text:


Abdulnour-Nakhoul S, Khuri RN, Nakhoul NL. (1994) Effect of norepinephrine on cellular sodium transport in Ambystoma kidney proximal tubule. Am J Physiol Renal Fluid Electrolyte Physiol. 267: F725–736.

Ahmad M, Medford RM. (1995) Evidence for the regulation of Na+,K+-ATPase a gene expression through the interaction of aldosterone and cAMP-inducible transcriptional factors.Steroids 60: 147–152.

Akbulut H, Akbulut KG, Gonul B. (1997) Malodialdehyde and glutathione in rat gastric mucosa and effects of exogenous melatonin. Dig Dis Sci. 42: 1381–1382.

Aperia A, Holtback U, Syren ML, Svensson LB, Fryckstedt J, Greengard P. (1994) Activation/deactivation of renal Na+,K+-ATPase: a final common pathway for regulation of natriuresis FASEB J. 8: 436–439.

Babitha GS, Peter MCS. (2010) Cortisol promotes and integrates the osmotic competence of the organs in North African catfish (Burchell): Evidence from in vivo and in situ approaches. Gen. Comp. Endocrinol. 168: 14-21.

Becker-Andre M, Wiesenberg I, Schaeren-Wiemers N, Andre E, Missbach JH, Saurat JH, Carlberg C. (1994) Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem. 269: 28531–28534.

Benziane B, Bjornholm M, Pirkmajer S, Austin L, Reginald, Kotova OL, Viollet B, Zierath RJ, Chibalin VA. (2012) Activation of AMP-activated protein kinase stimulates Na+,K+ ATPase Activity in skeletal muscle cells. J Biol Chem. 287: 23451–23463.

Beron J, Verrey F. (1994) Aldosterone induces early activation and late accumulation of Na+,K+-ATPase at surface of A6 cells. Am J Physiol Cell Physiol. 266: C1278–C1290.

Blask DE. (1993) Melatonin in oncology. In: Yu H-S, Reiter RJ (eds) Melatonin Biosynthesis, Physiological Effects and Clinical Applications. Boca Raton: CRC Press. pp. 447-477.

Blanchard DC , Spencer RL, Weiss SM, Blanchard RJ, McEwen B, Sakai RR. (1995) Visible burrow system as a model of chronic social stress: Behavioral and neuroendocrine correlates. Psychoneuroendocrinology 20: 117–134.

Brini M. (2003) Ca2+ signalling in mitochondria: mechanism and role in physiology and pathology. Cell Calcium 34: 399–405.

Bubenik GA. (2008) Thirty four years since the discovery of gastrointestinal melatonin. J Physiol Pharmacol.59 (Suppl 2): 33-35.

Bubenik GA, Hacker RR, Brown GM, Bartos L. (1999) Melatonin concentrations in the luminal fluid, mucosa, and muscularis of the bovine and porcine gastrointestinal tract. J Pineal Res. 26:56-63.

Cabeza J, Motilva V, Alarcon, de la Lastra CA. (2001) Mechanism involved in the gastric protection of melatonin on ischemia reperfusion-induced oxidative damage in rats. Life Sci. 68: 1405–1415.

Calì T, Ottolini D, Brini M. (2012) Mitochondrial Ca(2+) as a key regulator of mitochondrial activities. Adv Exp Med Biol. 942: 53-73.

Conti A, Maestroni GJM. (1995) The clinical neuroimmunotherapeutic role of melatonin in oncology. J Pineal Res. 19: 103-110.

Dean G E, Fishkes H, Nelson PJ, Rudnick G. (1984) The hydrogen ion-pumping adenosine triphosphatase of platelet dense granule membrane. Differences from F1F0- and phosphoenzyme-type ATPases. J Biol Chem. 259: 9569-9574.

Erlinger S. (1982) Does Na+,K+-ATPase have any role in bile secretion? Am J Physiol Gastrointest Liver Physiol. 243: G243-247.

Evans DH. (1998) The role of the intestine and gill in teleost fish osmoregulation. In: Epstein FH A Laboratory by the Sea: A Centennial History of the Mount Desert Island Biological Laboratory. Montana, USA: The River Press. Pp277-285.

Fe´ Raille E, Doucet A. (2001) Sodium-potassium-adenosinetriphosphate-dependent sodium transport in the kidney: hormonal control. Physiol. Rev. 81: 345-418.

Friedman PA, Gesek FA.(1995) Cellular calcium transport in renal epithelia: measurement, mechanisms, and regulation. Physiol Rev. 75: 429–471.

Gardner RC. (2003) Genes for magnesium transport. Curr Opin Plant Biol. 6: 263-267.

Garrhan PJ, Rega AF. (1998) Comprison between plasma membrane Ca2+ ATPase and Na+,K+ ATPase: Short review. Braz J Med Biol. 21: 1261.

Glavin GB, Pare WP, Sandbak T, Bakke HK, Murison R. (1994) Restraint stress in biomedical research: an update. Neurosci. Biobehav. Rev. 18: 223–249.

Guerra M, del Castillo AR, Battaner E, Mas M. (1981) Androgens stimulate preoptic area Na+,K+-ATPase activity in male rats. Neurosci Lett. 78: 97–100.

Guerrero JM, Reiter RJ. (2002) Melatonin-immune system relationships, Curr Top Med Chem. 2: 167–179.

Hediger HA, Romero MF, Peng JB, Rolfs A, Takanaga H, Bruford EA.(2004) The ABCs of solute carriers: Physiological, pathological and therapeutic implications of human membrane transport proteins. Introduction. Pfluegers Arch 447:465-468.

Herman JP, Adams D, Prewitt C.(1995) Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm. Neuroendocrinol 61:180–190.

Highman B, Altland PD. (1962) Serum enzyme and histopathologic changes in rats after cold exposure. Proc Soc Exp Biol Med. 109: 523–526.

Hoenderop JG, Bindels RJ. (2005) Epithelial Ca2+ and Mg2+ channels in health and disease. Am Soc Nephrol. 16: 15–26.

Ismail-Beigi F. (1998) Thyroid thermogenesis: Rgulation of (Na+, K+)-adenosine triphosphatase and active Na, K transport. Amer Zool. 28: 363-371.

Kasai H. (1999) Comparative biology of Ca2+-dependent exocytosis: implications of kinetic diversity for secretary function. Trends Neurosci 22: 88-93.

Kathol RG, Anton R, Noyes R, Gehris T. (1989) Direct comparison of urinary free cortisol excretion in patients with depression and panic disorder. Biol Psychiatry. 25: 873–878.

Kawashima K, Miwa Y, Fujimoto K, Oohata H, Nishino H , Koike H.(1987) Antihypertensive action of melatonin in the spontaneously hypertensive rat. Clin Exp Hyprtens A. 9: 1121-1131.

Koob GF, Heinrichs SC. (1999) A role for corticotropin releasing factor and urocortin in behavioral responses to stressors. Brain Res. 848: 141–152.

Kovacheva-Ivanova S, Bakalova R, Ribarov SR. (1994) Immobilization stress enhances lipid peroxidation in the rat lungs. Gen Physiol Biophys. 13: 469–482.

Kvetnoy IM, Ingel IE, Kvetnaia TV, Malinovskaya NK, Rapoport SI, Raikhlin NT, Trofimov AV, Yuzhakov VV. (2002) Gastrointestinal melatonin: cellular identification and biological role. Neuroendocrinol Lett. 23: 121-132.

Kubota T, Shindo Y, Tokuno K, Komatsu H, Ogawa H, Kudo S, Kitamura Y, Suzuki K, Oka K. (2005). Mitochondria are intracellular magnesium stores: investigation by simultaneous fluorescent imagings in PC12 cells. Biochim Biophys Acta. 1744: 19-28.

Kultz D. (2003) Evolution of the cellular stress proteome: from monophyletic origin to ubiquitous function. J Exp Biol. 206: 3119–3124.

Laurant P, Touyz RM. (2000) Physiological and pathophysiological role of magnesium in the cardiovascular system: implications in hypertension. J Hypertens. 18: 1177-1191.

Lee MG, Xu X, Zeng W, Diaz J, Kuo TH, Wuytack F, Raeymaekers L, Muallem S. (1997) Polarized expression of Ca2+ pumps in pancreatic and salivary gland cells. J Biol Chem. 272: 15771-15776.

Lehninger AL. (1988) Biochemistry: The Molecular Basis of Cell Structure and Function. 2nd Edn. Ludhiana, New Delhi: Kalyani Publishers.

Liberman UA, Asano Y, Lo CS, Edelman IS. (1979) Relationship between Na+-dependent respiration and of Na+,K+-ATPase activity in the action of thyroid hormone on rat jejunal mucosa. Biophys J. 27: 127-144.

Lopez A, Garcıa JA, Escames G, Venegas C, Ortiz F, Lopez LC, Acuna-Castroviejo D (2009) Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J Pineal Res. 46:188–198.

Mahendravarma B, Surendrakumar RB. (1996) Enhancement of ATPases of fetal brain of mouse exposed to ultrasound. Biomedicine 16: 27–33.

Maillot C, Million M, Wei JY, Gauthier A, Tache´ Y. (2000) Peripheral corticotrophin releasing factor and stress-stimulated colonic motor activity involve type 1 receptor in rats. Gastroenterology 119: 1569–1579.

Marti O, Gavalda A, Jolin T, Armario A. (1993) Effect of regularity of exposure to chronic immobilization stress on the circadian pattern of pituitary adrenal hormones, growth hormone, and thyroid stimulating hormone in the adult male rat. Psychoneuroendocrinology 18: 67–77.

Matejovska I, Bernaskova K, Krysl D, Mares J. (2008) Influence of melatonin pre-treatment and preconditioning by hypobaric hypoxia on the development of cortical photothrombotic ischemic lesion. Physiol Res. 57: 283-288.

McBride BW, Kelly JM. (1990) Energy cost of absorption and metabolism in the ruminant gastrointestinal tract and liver: a review. J Anim Sci. 68: 2997-3010.

Meltzer HY. (1971) Plasma creatine phosphokinase activity, hypothermia,and stress. Am J Physiol. 221: 896–901.

Nishi T, Forgac M. (2002) The vacuolar (H+)-ATPases--nature’s most versatile proton pumps. Nat Rev Mol Cell Biol. 3: 94-103.

Nishida S. (2005) Metabolic effects of melatonin on oxidative stress and diabetes mellitus. Endocrine. 27: 131-136.

Oishi K, Yokoi M, Maekawa S, Sodeyama C, Shiraishi T, Kondo R, Kuriyama T, Machida K.(1999) Oxidative stress and haematological changes in immobilized rats. Acta Physiol Scand. 165: 65–69.

Pare WP, Glavin GB. (1986) Restraint stress in biomedical research: a review. Neurosci Biobehav Rev. 10: 339–370.

Parvez S, Sayeed I, Raisuddin S. (2006) Decreased gill ATPase activities in the freshwater fish Channa punctata exposed to a diluted paper mill effluent. Ecotoxicol Enviorn Saf. 65: 62–66.

Pearl W, Balazs T, Buyske DA. (1966) The effect of stress on serum transaminase activity in the rat. Life Sci. 5: 67–74.

Peter MCS. (2013) Understanding the adaptive response in vertebrates: The phenomenon of ease and ease response during post-stress acclimation. Gen Comp Endocrinol 181: 59-64.

Peter MCS, Lock RAC, Wendelaar Bonga SE. (2000). Evidence for an osmoregulatory role of thyroid hormones in the freshwater Mozambique tilapia, Oreochromis mossambicus. Gen Comp Endocrinol 120: 157-167.

Peter MCS, Mini VS, Bindulekha DS, Peter VS.(2014) Short-term in situ effects of prolactin and insulin on ion transport in liver and intestine of freshwater climbing perch (Anabas testudineus Bloch) J Endocrinol Reprod 18 : 47- 58.

Reiter RJ, Tan DX, Manchester LC, Lopez-Burillo S, Sainz RM, Mayo JC. (2003) Melatonin: detoxification of oxygen and nitrogen-based toxic reactants. Adv Exp Med Biol .527:539-548.

Reiter RJ, Tan DX, Terron MP, Flores LJ, Czarnock Z. (2007) Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions. Acta Biochim Pol .54:1-9.

Romani AM, Maguire ME. (2002) Hormonal regulation of Mg2+ transport and homeostasis in eukaryotic cells. Biometals. 15: 271-283.

Ruszymah BH, Khalid BA.(1999) A survey of recent results concerning glycyrrhizic acid in stress and adaptation. Med J Islamic Acad Sci. 12: 25–28.

Sánchez O, Arnau A, Pareja M, Poch E, Ramirez I, Soley M. (2002) Acute stress-induced tissue injury in mice: differences between emotional and social stress. Cell Stress Chaperones. 7: 36–46.

Shi Y, Devadas S, Greeneltch KM, Yin D, Allan MR, Zhou JN. (2003) Stressed to death: implication of lymphocyte apoptosis for psychoneuroimmunology. Brain Behav. Immun. 17:S18–S26.

Sterling P, Eyer J. (1988) Allostasis: a new paradigm to explain arousal pathology. In: Fisher S, Reason J (eds) Handbook of Life Stress, Cognition and Health, New York, NY, USA: John Wiley & Sons, pp 631–651.

Stinnett GS, Seasholtz AF. (2010) Stress and emotionality. Koob GF, Le Moal M, R. F. Thompson RF (eds) Encyclopedia of Behavioral Neuroscience, San Diego, CA, USA: Elsevier. pp 316–321.

Tache´ Y. (1989) Stress-induced alterations of gastric emptying. In: Bueno L, Collins S, Junien JL (eds) Stress and Digestive Motility, Montrouge, France: John Libbey Eurotext. pp 123–132.

Verrey F, Summa V, Heitzmann D, Mordasini D, Vandewalle A, Féraille E, Zecevic M. (2003) Short-term aldosterone action on Na,K-ATPase surface expression: role of aldosterone-induced SGK1? Ann N Y Acad Sci. 986: 554-561.

Warren MA, Kucharski LM, Veenstra A, Shi L, Grulich PF, Maguire ME. (2004) The CorA Mg2+ transporter is a homotetramer. J Bacteriol. 186: 4605-4612.

Wasserman RH. (2005) Vitamin D and the intestinal absorption of calcium: A view and overview. In: Feldman D, Pike JW, Glorieux FH (eds.) Vitamin D, 2nd ed. San Diego, CA, USA: Elsevier. pp 441–428.

Wilson BS, Pfeiffer JR, Smith AJ, Oliver JM, Oberdorf JA, Wojcikiewicz RJH. (1998) Calcium dependent clustering of inositol 1, 4, 5-triphosphate receptors. Mol Biol Cell. 9: 1465-1478.


  • There are currently no refbacks.