Drosophila as a Model System for Cardiology: The Case of Melatonin and Heartbeat Regularity
Main Article Content
Abstract
Our objective in this review is to summarize evidence of the strong cardiac rhythmicity-enhancing power of melatonin in the Drosophila melanogaster model system and discuss the implications of these findings in the context of fundamental cardiac pacemaker function and potential clinical applications. Drosophila has proven itself as an exceptional research organism given the far-reaching genetic and molecular tools it offers. We consider details of the fly's myogenic, ion-channel-based pacemaker and summarize aspects of its neurohomonal control. Melatonin, in the context of cardiology, has predominately been associated with its antioxidant properties in the prevention of reperfusion damage after infarct, but we have strongly confirmed the few reports of its effect strengthening rhythmicity. We discuss our clear results showing that melatonin is capable of converting normal noisy heartbeat to an extremely regular oscillator. It rescues the very uneven beat of the hearts of flies bearing a serious mutation in a gene encoding one of its core pacemaker ion channels. Possible mechanisms for these effects are considered.
Keywords:
Drosophila pacemaker, ion channels, heartbeat regularity, melatonin
Article Details
How to Cite
DOWSE, H.; VANKIRK, T.
Drosophila as a Model System for Cardiology: The Case of Melatonin and Heartbeat Regularity.
Medical Research Archives, [S.l.], v. 10, n. 5, june 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2808>. Date accessed: 05 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i5.2808.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Yamaguchi M, Yoshida H. Drosophila as a Model Organism. Drosophila models for human diseases In: Advances in Experimental Medicine and Biology. Springer. 2018:1-10.
2. Adams MD, et al. The genome sequence of Drosophila melanogaster. Science 2000;287: 2185-2195.
3. Bier E, Bodmer, R. Drosophila, An emerging model for cardiac disease. Gene. 2004;342:1-11.
4. Reiter RJ, Tan D-X. Melatonin: a Novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res. 2003;58:10–9.
5. Qian L, Liu J, Bodmer R. Cardiovascular development. Adv Dev Biol. 2003;18:1–29.
6. Taghli-Lamallem, O, Plantie E, Jagla K. Drosophila in the heart of understanding cardiac diseases: Modeling channelopathies and cardiomyopathies in the fruitfly. J Cardiovasc Dev and Dis. 2016;3:7-28.
7. Birse R, Choi J, Reardon K, et al. High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila. Cell Metabolism. 2010;12:533-544.
8. Diop S, Bodmer R. Drosophila as a model to study the genetic mechanisms of obesity-associated heart dysfunction. J Cell Mol Med. 2012;16:966-971.
9. Bodmer R, Venkatesh T V. Heart development in Drosophila and vertebrates : Conservation of molecular mechanisms. Dev Genet. 1998;186:181–186.
10. Bodmer R, Wessels RJ, Johnson E, Dowse H. Heart development and function. In: L.I. Gilbert, K. Iatrou SG, editor. Comprehensive Molecular Insect Science. 2005 London: Elsevier.
11. Miller A. The internal anatomy and histology of the imago of Drosophila melanogaster. In: Demerec M, editor. Biology of Drosophila. New York and London: John Wiley & Sons. 1950;420–534.
12. Rizki TM. The circulatory system and associated cells and tissues. In: Ashburner M; WT, editor. The Genetics and Biology of Drosophila. London: Academic Press. 1978;1839–1845.
13. Curtis NJ, Ringo JM, Dowse HB. Morphology of the pupal heart, adult heart, and associated tissues in the fruit fly, Drosophila melanogaster. J Morphol. 1999;240:225–35.
14. Wasserthal LT. Drosophila flies combine periodic heartbeat reversal with a circulation in the anterior body mediated by a newly discovered anterior pair of ostial valves and “venous” channels. J Exp Biol. 2007;210:3707–19.
15. Prosser, C., Brown, F. Jr., Comparative Animal Physiology, 2nd edn. 1961 Little and Brown, New York.
16. Miller TA. 1985. Heart and diaphragms. In: GA Kerkut LG, editor. Comprehensive Insect Physiology, Biochemistry, and Pharmacology. New York: Permagon. p. 1985;119–130.
17. Gu GG, Singh S. Pharmacological analysis of heartbeat in Drosophila. J Neurobiol. 1995;28:269–80.
18. Dowse H, Ringo J, Power et al. A congenital heart defect in Drosophila caused by an action-potential mutation. J Neurogenet. 1995;10:153–68.
19. White LA, Ringo, JM, Dowse HB. Effects of deuterium oxide and temperature on heart rate in Drosophila melanogaster. J Comp Physiol B. 1992;162:278–83.
20. Johnson E, Ringo J, Bray N, Dowse H. Genetic and pharmacological identification of ion channels central to the Drosophila cardiac pacemaker. J. Neurogenet. 1998;12:1–24.
21. Irisawa H, Brown HF, Giles W. Cardiac pacemaking in the sinoatrial node. Physiol Rev. 1993;73:197–227.
22. Bers, DM, Excitation-Contraction Coupling and Cardiac Contractile Force. Kluwer Academic Publishers Group, Dordecht 2001.
23. Dowse HB. Analyses for Physiological and Behavioral Rhythmicity. In: Methods in Enzymology. 2009;141–174.
24. Chatfield C. The Analysis of Time Series. Taylor and Francis 1980.
25. Levine JD, Funes P, Dowse HB, Hall JC. Signal analysis of behavioral and molecular cycles. BMC Neurosci. 2002;3:1.
26. Burg, J.P., Maximum entropy spectral analysis. In: Childers, G. (Ed.), Modern Spectral Analysis. IEEE Press, New York 1967;34–41.
27. Ulrych, T, Bishop, T, 1975. Maximum entropy spectral analysis and autoregressive decomposition. Rev Geo-Phy Space Phys. 1975;13:183–200.
28. VanKirk T, Powers E, Dowse HB. Melatonin increases the regularity of cardiac rhythmicity in the Drosophila heart in both wild-type and strains bearing pathogenic mutations. J Comp Physiol B, 2017;187(1):63-78 doi:10.1007/s00360-016-1019-8
29. Garcia M, King V, Siegl P. Binding of Ca2+ entry blockers to cardiac sarcolemmal membrane vesicles. J Biol Chem. 1986;261:8164-8157.
30. Ghoa M, Mallart M. Two distinct calcium-activated potassium currents in larval muscle fibers of Drosophila melanogaster. 1986;407:526-533.
31. Wu C-F, Ganetzky B, Jan LY, Jan YN, Benzer S. A Drosophila mutant with a temperature-sensitive block in nerve conduction. Proc Natl Acad Sci. U. S. A. 1978;75:4047–4051.
32. Kernan MJ, Kuroda MI. et al. napts, a mutation affecting sodium channel activity in Drosophila, is an allele of mle, a regulator of X chromosome transcription. Cell. 1991;66:949–959.
33. Suzuki DT, Grigliatti T, Williamson R. Temperature-sensitive mutations in Drosophila melanogaster, VII. A mutation (parats) causing a reversible adult paralysis. Proc Natl Acad Sci USA. 1971;68:890–893.
34. Kuroda M, Kernan M, Kreber R, et al. The maleless protein associates with the X chromosome to regulate dosage compensation in Drosophila. Cell. 1991;66:935-947.
35. Wu C.-F, Ganetzky B. Genetic alteration of nerve membrane excitability in temperature-sensitive paralytic mutants of Drosophlia melanogaster. Nature. 1980;286:814-816.
36. Wright T. The genetics of dopa decarboxylase and α-methyl dopa sensitivity in Drosophila melanogaster. Am Zool. 1977;17:707-721.
37. Livingston M, Tempel B. Genetic dissection of monoamine neurotransmitter synthesis in Drosophila. Nature 1983;303:67-70.
38. Tully, T., Quinn, W.G., Classical conditioning and retention in normal and mutant Drosophila melanogaster. J Comp Physiol A. 1985;157:263–277.
39. Feany M., Quinn W. A neuropeptide gene defined by the Drosophila memory mutant amnesiac. Science. 1995;268:869–873.
40. Elkins T, Ganetzky B, Wu C-F. A Drosophila mutation that eliminates a calcium-dependent potassium current. Proc Natl Acad Sci U. S. A. 1986; 83:8415–9.
41. Atkinson NS, Robertson G, Ganetzky B. A component of calcium-activated potassium channels encoded by the Drosophila slo locus. Science 1991;253:551–555.
42. Singh S, Wu, C.-F. Complete separation of four potassium currents in Drosophila. Neuron, 1989;2:1325–1329.
43. Johnson E, Ringo J, Dowse H. Native and heterologous neuropeptides are cardioactive in Drosophila melanogaster. J Insect Physiol. 2000;46:1229–1236.
44. Johnson E, Ringo J, Dowse H. Modulation of Drosophila heartbeat by neurotransmitters. J Comp Physiol B. 1997;167:89–97.
45. Kaplan WD, Trout WE. The behavior of four neurological mutants of Drosophila. Genetics 1969;61:399–409.
46. Warmke J, Drysdale R, Ganetzky B. A distinct potassium channel polypeptide encoded by the Drosophila eag locus. Science 1991;252:1560–1562.
47. Engel JE, Wu C-F. Interactions of membrane excitability mutations affecting potassium and sodium currents in the flight and giant fiber escape systems of Drosophila. J Comp Physiol A. 1992;171:93–104.
48. Brüggemann A, Pardo L, Stühmer W, Pongs O. Ether-à-go-go encodes a voltage-gated channel permeable to K+ and Ca2+ and modulated by cAMP. Nature 1993;365:445–448.
49. Brown H, DiFrancesco D, Noble S. How does adrenaline accelerate the heart? Nature. 1979;280:235-236.
50. Von Schilcher F. The behavior of cacophony, a courtship song mutant in Drosophila melanogaster. Behav Biol. 1976;17:187–96.
51. Smith L, Wang X, et al. A Drosophila calcium channel alpha1 subunit gene maps to a genetic locus associated with behavioral and visual defects. J Neurosci. 1996;16:7868–7879.
52. Smith L, Peixoto A, et al. Courtship and visual defects of cacophony mutants reveal functional complexity of a calcium-channel alpha1 subunit in Drosophila. Genetics. 1998;149:1407–1426.
53. Ray VM, Dowse HB. Mutations in and deletions of the Ca2+ channel-encoding gene cacophony, which affect courtship song in Drosophila, have novel effects on heartbeating. J Neurogenet. 2005;19:39–56.
54. Ashcroft FM. 2000. Ion Channels and Disease. Academic Press.
55. Hille B. Ionic Channels of Excitable Membranes. 3rd ed. Sinauer, Sunderland, editors. Mass. 2001.
56. Olivera BM, Miljanich GP, Ramachandran J, Adams ME. Calcium channel diversity and neurotransmitter release: the omega-conotoxins and omega-agatoxins. Annu Rev Biochem. 1994;63:823–67.
57. Kaplan WD, Trout WE. The behavior of four neurological mu1ts of Drosophila. Genetics. 1969;61:399–409.
58. Warmke JW, Ganetzky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U. S. A. 1994;91:3438–42.
59. Thompson SH. Three pharmacologically distinct potassium channels in molluscan neurones. J Physiol. 1977;265:465–488.
60. Moczydlowski E, Lucchesi K, Ravindran A. 1988. An emerging pharmacology of peptide toxins targeted against potassium channels. J Membr Biol. 1988;105:95–111.
61. Elkins T, Ganetzky B, Wu C-F. A Drosophila mutation that eliminates a calcium-dependent potassium current. Proc Natl Acad Sci U. S. A. 1986;83:8415–9.
62. Fozzard HA. The Heart and cardiovascular system: scientific foundations. Raven Press. 1986.
63. Littleton JT, Ganetzky B. Ion channels and synaptic organization: analysis of the Drosophila genome. Neuron 2000;26:35–43.
64. Lipsius SL, Hüser J, Blatter L. Intracellular Ca2+ release sparks atrial pacemaker activity. News Physiol Sci. 2001;16:101–106.
65. Johnson E, Sherry T, Ringo J Dowse H. 2002. Modulation of the cardiac pacemaker of Drosophila: cellular mechanisms. J Com. Physiol B Biochem Syst Environ Physiol. 2002;172:227–236.
66. Johnson E, Ringo J, Dowse H. Native and heterologous neuropeptides are cardioactive in Drosophila melanogaster. J Insect Physiol. 2000;46:1229-1236.
67. Gagnon A, Kallal L, Benovic. Role of clathrin-mediated endocytosis in agonist-induced downregulation of the β2- adrenergic receptor. J Biol Chem. 1998;273:6976-6981.
68. Grigliatti T, Hall L, et al. Temperature-sensitive mutations in Drosophila melanogaster XIV A selection of immobile adults. Molec Gen Genet. 1973;120:107-114.
69. Chen MS, Obar RA, et al. Multiple forms of dynamin are encoded by shibire, a Drosophila gene involved in endocytosis. Nature, 1991;351:583-586.
70. van der Bliek A, Myerowitz E. Dynamin-like protein encoded by the Drosophila shbire gene associated with vesicular traffic. Nature. 1991;351:411-414.
71. Masur S, Kim Y-T, Wu C-F. REversible lihigibion of endocytosis in cultured neurons from the temperature-sensitive mutation shibirets. J Neurogenet. 1990;6:191-206.
72. Lerner AB, Case JD, Takahashi, et al.. Isolation of melatonin, the pineal gland factor That lightens melanocytes. J Am Chem Soc. 1958;80:2587–2587.
73. McCord CP, Allen FP. Evidences associating pineal gland function with alterations in pigmentation. J. Exp. Zool. 1917;23:207–224.
74. Kitay JI, Altschule MD. The pineal gland: a review of the physiologic literature. Published for the Commonwealth Fund by Harvard University Press 1954.
75. Hardeland R, Cardinali DP, et al. Melatonin--a pleiotropic, orchestrating regulator molecule. Prog Neurobiol. 2011;93:350–84.
76. Man GC-W, Wong JH, et al. Abnormal melatonin receptor 1B expression in osteoblasts from girls with adolescent idiopathic scoliosis. J Pineal Res. 2011;50:395–402.
77. Reiter RJ. Melatonin: the chemical expression of darkness. Mol Cell Endocrinol. 1991;79:C153–8.
78. Yu HS, Hernandez V, Haywood M, Wong CG. Melatonin inhibits the proliferation of retinal pigment epithelial (RPE) cells in vitro. In Vitro Cell Dev Biol Anim. 1993;29A:415–418.
79. Pandi-Perumal SR, Trakht I, et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008;85:335–53.
80. Slominski A, Tobin DJ, et al. Melatonin in the skin: synthesis, metabolism and functions. Trends Endocrinol Metab. 2008;19:17–24.
81. Leja-Szpak A, Jaworek J, et al. Melatonin induces pro-apoptotic signaling pathway in human pancreatic carcinoma cells (PANC-1). J Pineal Res. 2010;49:248–255.
82. Celinski K, Konturek SJ, et al. Melatonin or L-tryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole. J. Pineal Res. 2011;50:389–94.
83. Reppert SM. Melatonin Receptors: Molecular Biology of a New Family of G Protein-Coupled Receptors. J Biol Rhythms 1997;12:528–531.
84. Dubocovich ML, Masana MI, Benloucif S. Molecular pharmacology and function of melatonin receptor subtypes. Adv Exp Med Biol. 1999;460:181–90.
85. Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 2005;27:101–10.
86. Imbesi M, Arslan AD, Yildiz S et al. The melatonin receptor MT1 is required for the differential regulatory actions of melatonin on neuronal “clock” gene expression in striatal neurons in vitro. J Pineal Res. 2009;46:87–94.
87. Shiu SYW, Pang B, Tam CW, Yao K-M. Signal transduction of receptor-mediated antiproliferative action of melatonin on human prostate epithelial cells involves dual activation of Gα(s) and Gα(q) proteins. J Pineal Res. 2010;49:301–11.
88. Reiter RJ. Functional aspects of the pineal hormone melatonin in combating cell and tissue damage induced by free radicals. Eur J Endocrinol. 1996;134:412–20.
89. Tan D, Reiter RJ, Manchester LC, Yan M, et al. 2002. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem. 2002;2:181–97.
90. Silva SO, Rodrigues MR, Ximenes VF, et al. Neutrophils as a specific target for melatonin and kynuramines: effects on cytokine release. J Neuroimmunol. 2004;156:146–52.
91. Mayo JC, Sainz RM, Tan D-X, et al. Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol. 2005;165:139–49.
92. Manda K, Ueno M, Anzai K. AFMK, a melatonin metabolite, attenuates X-ray-induced oxidative damage to DNA, proteins and lipids in mice. J Pineal Res. 2007;42:386–393.
93. Manda K, Ueno M, Anzai K. Space radiation-induced inhibition of neurogenesis in the hippocampal dentate gyrus and memory impairment in mice: ameliorative potential of the melatonin metabolite, AFMK. J Pineal Res. 2008;45:430–8.
94. Hardeland R, Tan D-X, Reiter RJ. Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines. J Pineal Res. 2009;47:109–26.
95. Schaefer M, Hardeland R. The melatonin metabolite N-acetyl-5-methoxykynuramine is a potent singlet oxygen scavenger. J Pineal Res. 2009;46:49–52.
96. Hickman AB, Klein DC, Dyda F. Melatonin Biosynthesis. Mol Cell. 1999;3:23–32.
97. Hintermann E, Jeno P, Meyer U. Isolation and characterization of an arylalkylamine N-acetyltransferase from Drosophila melanogaster. FEBS Lett. 1995;375:148–150.
98. Brodbeck D, Amherd R, Callaerts P. Molecular and biochemical characterization of the aaNAT1 (Dat) locus in Drosophila melanogaster: differential expression of two gene products. DNA Cell Biol. 1998;17:621–33.
99. Amherd R, Hintermann E, Walz D, Affolter M, Meyer U. Purification, cloning, and characterization of a second arylalkylamine N-acetyltransferase from Drosophila melanogaster. DNA Cell Biol. 2000;19:697–705.
100. Hardeland R. Extended Signaling by Melatonin. Cell Cellular Lif Sci J. 2018;3:00123.
101. Padayatty S. et al. Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention. Journal of the American College of Nutrition. 22;1:18-35.
102. Tan DX, Reiter RJ, et al. Ischemia/perfusion induced arrhythmia in the isolated rat heart: prevention my melatonin. J Pineal Res. 1998;25:184-191.
103. Bertuglia S, Reiter RJ. Melatonin reduces ventricular arrhythmias and preserves capillary perfusion during ischemia-reperfusion events in cardiomyopathic hamsters. J Pineal Res. 2007;42:55–63.
104. Diez ER, Prados LV, Carrión A, et al. A novel electrophysiologic effect of melatonin on ischemia/reperfusion-induced arrhythmias in isolated rat hearts. J. Pineal Res. 2009;46:155–160.
105. Benova T, Knezl V, Viczenczova C, et al. Acute anti-fibrillating and defibrillating potential of atorvastatin, melatonin, eicosapentaenoic acid and docosahexaenoic acid demonstrated in isolated heart model. J Physiol Pharmacol. 2015;66:83–89.
106. Goldberger AL. Heartbeat Chaotic or Homestatic? Physiology. 1991;6:87-91.
107. `Lim H-Y, Wang W, et al. ROS Regulate Cardiac Function via a Distinct Paracrine Mechanism. Cell Reports. 2014;7:35-44.
108. Symoens J. Ketanserin: a novel cardiovascular drug. Blood Coagul Fibrinolysis. 1990;1:219-224.
109. Audinot V, Mailliet F, Lahaye-Brasseur C, et al. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn Schmiedebergs Arch Pharmacol. 2003;367:553–561.
110. Bellés X. Beyond Drosophila: RNAi in vivo and functional genomics in insects. Annu Rev Entomol. 2010;55:111–28.
111. Bodmer R. The gene tinman is required for specification of the heart and visceral muscles in Drosophila. Development. 1993;118:719-729.
112. Venkatesh TV, Park M, Ocorr K, et al. Cardiac enhancer activity of the homeobox gene tinman depends on CREB consensus binding sites in Drosophila. Genesis. 2000;13:55-66.
113. Wessells RJ, Bodmer R. Screening assays for heart function mutants in Drosophila. Biotechniques. 2004;37:58–60, 62, 64 passim.
114. Kunwar PS, Starz-Gaiano M, et al. Tre1, a G Protein-coupled receptor, directs transepithelial migration of Drosophila germ cells. PLoS Biol. 2003;1(3):e80.
115. Rezzani R, Rodella LF, Bonomini F, et al. Beneficial effects of melatonin in protecting against cyclosporine A-induced cardiotoxicity are receptor mediated. J Pineal Res. 2006;41:288–95.
116. Yu L, Sun Y, Cheng L, et al. 2014. Melatonin receptor-mediated protection against myocardial ischemia/reperfusion injury: Role of SIRT1. J Pineal Res. 2014;57:228–238.
117. Lochner A. Short and Long Term Effects of Melatonin on Myocardial Post-Ischemic Recovery. J. Pineal Res. 2006;40:56–63.
118. Ding CN1, Cao YX, Zhou L, et al. Effects of microinjection of melatonin and its receptor antagonists into anterior hypothalamic area on blood pressure and heart rate in rats. Acta Pharmacol. 2001;Sin.22:997-1002.
119. Glass L. Introduction to Controversial Topics in Nonlinear Science: Is the Normal Heart Rate Chaotic? Chaos. 2009;19:028501.`
120. Wu G-Q, Arzeno NM, et al. Chaotic Signatures of Heart Rate Variability and Its Power Spectrum in Health, Aging and Heart Failure. PLoS ONE. 2009;4:e4323.
121. Vinogradova T. Rhythmic Ryanodine Receptor Ca2+ releases during diastolic depolarization of sinoatrial pacemaker cells do not require membrane depolarization. Circ Res. 2004;94:802-809.
122. Maltsev V, Lakatta E. Dynamic Interactions of an Intracellular Ca2+ Clock and Membrane Ion Channel Clock Underlie Robust Initiation and Regulation of Cardiac Pacemaker Function. Cardiovascular Res. 2008;77:274-284.
123. Lakatta E, DiFrancesco D. JMCC Point-Counterpoint: What Keeps us Ticking, a Funny Current, a Calcium Clock, or Both? J. Mol. Cell Cardiol. 2009;47:157-170.
124. Lakatta, E. Maltsev V, Vinogradova T. A Coupled SYSTEM of Intracellular Ca2+ Clocks and Surface Membrane Voltage Clocks Controls the Timekeeping Mechanism of the Heart's Pacemaker. Circulation Res. 2010;106:659-673.
125. Wolk R. Arrhythmogenic mechanisms in left ventricular hypertrophy. Europace 2000;2:216–223.
126. Sanyal S, Consoulas C, et al. Analysis of conditional paralytic mutants in Drosophila SERCA reveals novel mechanism for regulating membrane excitability. Genetics. 2005;DOI10.1534.
127. Sanyal, S., T. Jennings, H. Dowse, and M. Ramaswami. Conditional mutations in SERCA, the Sarco-endoplasmic reticulum Ca2+-ATPase, alter heart rate and rhythmicity in Drosophila. J. Comp. Physiol. B. 2005:176: 253-263.
128. Abraham M, Wolf M. Disruption of Sarcoendoplasmic Reticulum Calcium ATPase Function in Drosophila Leads to Cardiac Dysfunction PLoS ONE. 2013;8:e77785.
129. VanKirk T. Effects of melatonin on heartbeat and possible identification of a melatonin receptor in Drosophila melanogaster. Doctoral Thesis University of Maine. 2015.
130. Sullivan, K., Scott, K., Zuker, C., Rubin, G., The ryanodine receptor is essential for larval development in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 2000;97:5492–5497.
2. Adams MD, et al. The genome sequence of Drosophila melanogaster. Science 2000;287: 2185-2195.
3. Bier E, Bodmer, R. Drosophila, An emerging model for cardiac disease. Gene. 2004;342:1-11.
4. Reiter RJ, Tan D-X. Melatonin: a Novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res. 2003;58:10–9.
5. Qian L, Liu J, Bodmer R. Cardiovascular development. Adv Dev Biol. 2003;18:1–29.
6. Taghli-Lamallem, O, Plantie E, Jagla K. Drosophila in the heart of understanding cardiac diseases: Modeling channelopathies and cardiomyopathies in the fruitfly. J Cardiovasc Dev and Dis. 2016;3:7-28.
7. Birse R, Choi J, Reardon K, et al. High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila. Cell Metabolism. 2010;12:533-544.
8. Diop S, Bodmer R. Drosophila as a model to study the genetic mechanisms of obesity-associated heart dysfunction. J Cell Mol Med. 2012;16:966-971.
9. Bodmer R, Venkatesh T V. Heart development in Drosophila and vertebrates : Conservation of molecular mechanisms. Dev Genet. 1998;186:181–186.
10. Bodmer R, Wessels RJ, Johnson E, Dowse H. Heart development and function. In: L.I. Gilbert, K. Iatrou SG, editor. Comprehensive Molecular Insect Science. 2005 London: Elsevier.
11. Miller A. The internal anatomy and histology of the imago of Drosophila melanogaster. In: Demerec M, editor. Biology of Drosophila. New York and London: John Wiley & Sons. 1950;420–534.
12. Rizki TM. The circulatory system and associated cells and tissues. In: Ashburner M; WT, editor. The Genetics and Biology of Drosophila. London: Academic Press. 1978;1839–1845.
13. Curtis NJ, Ringo JM, Dowse HB. Morphology of the pupal heart, adult heart, and associated tissues in the fruit fly, Drosophila melanogaster. J Morphol. 1999;240:225–35.
14. Wasserthal LT. Drosophila flies combine periodic heartbeat reversal with a circulation in the anterior body mediated by a newly discovered anterior pair of ostial valves and “venous” channels. J Exp Biol. 2007;210:3707–19.
15. Prosser, C., Brown, F. Jr., Comparative Animal Physiology, 2nd edn. 1961 Little and Brown, New York.
16. Miller TA. 1985. Heart and diaphragms. In: GA Kerkut LG, editor. Comprehensive Insect Physiology, Biochemistry, and Pharmacology. New York: Permagon. p. 1985;119–130.
17. Gu GG, Singh S. Pharmacological analysis of heartbeat in Drosophila. J Neurobiol. 1995;28:269–80.
18. Dowse H, Ringo J, Power et al. A congenital heart defect in Drosophila caused by an action-potential mutation. J Neurogenet. 1995;10:153–68.
19. White LA, Ringo, JM, Dowse HB. Effects of deuterium oxide and temperature on heart rate in Drosophila melanogaster. J Comp Physiol B. 1992;162:278–83.
20. Johnson E, Ringo J, Bray N, Dowse H. Genetic and pharmacological identification of ion channels central to the Drosophila cardiac pacemaker. J. Neurogenet. 1998;12:1–24.
21. Irisawa H, Brown HF, Giles W. Cardiac pacemaking in the sinoatrial node. Physiol Rev. 1993;73:197–227.
22. Bers, DM, Excitation-Contraction Coupling and Cardiac Contractile Force. Kluwer Academic Publishers Group, Dordecht 2001.
23. Dowse HB. Analyses for Physiological and Behavioral Rhythmicity. In: Methods in Enzymology. 2009;141–174.
24. Chatfield C. The Analysis of Time Series. Taylor and Francis 1980.
25. Levine JD, Funes P, Dowse HB, Hall JC. Signal analysis of behavioral and molecular cycles. BMC Neurosci. 2002;3:1.
26. Burg, J.P., Maximum entropy spectral analysis. In: Childers, G. (Ed.), Modern Spectral Analysis. IEEE Press, New York 1967;34–41.
27. Ulrych, T, Bishop, T, 1975. Maximum entropy spectral analysis and autoregressive decomposition. Rev Geo-Phy Space Phys. 1975;13:183–200.
28. VanKirk T, Powers E, Dowse HB. Melatonin increases the regularity of cardiac rhythmicity in the Drosophila heart in both wild-type and strains bearing pathogenic mutations. J Comp Physiol B, 2017;187(1):63-78 doi:10.1007/s00360-016-1019-8
29. Garcia M, King V, Siegl P. Binding of Ca2+ entry blockers to cardiac sarcolemmal membrane vesicles. J Biol Chem. 1986;261:8164-8157.
30. Ghoa M, Mallart M. Two distinct calcium-activated potassium currents in larval muscle fibers of Drosophila melanogaster. 1986;407:526-533.
31. Wu C-F, Ganetzky B, Jan LY, Jan YN, Benzer S. A Drosophila mutant with a temperature-sensitive block in nerve conduction. Proc Natl Acad Sci. U. S. A. 1978;75:4047–4051.
32. Kernan MJ, Kuroda MI. et al. napts, a mutation affecting sodium channel activity in Drosophila, is an allele of mle, a regulator of X chromosome transcription. Cell. 1991;66:949–959.
33. Suzuki DT, Grigliatti T, Williamson R. Temperature-sensitive mutations in Drosophila melanogaster, VII. A mutation (parats) causing a reversible adult paralysis. Proc Natl Acad Sci USA. 1971;68:890–893.
34. Kuroda M, Kernan M, Kreber R, et al. The maleless protein associates with the X chromosome to regulate dosage compensation in Drosophila. Cell. 1991;66:935-947.
35. Wu C.-F, Ganetzky B. Genetic alteration of nerve membrane excitability in temperature-sensitive paralytic mutants of Drosophlia melanogaster. Nature. 1980;286:814-816.
36. Wright T. The genetics of dopa decarboxylase and α-methyl dopa sensitivity in Drosophila melanogaster. Am Zool. 1977;17:707-721.
37. Livingston M, Tempel B. Genetic dissection of monoamine neurotransmitter synthesis in Drosophila. Nature 1983;303:67-70.
38. Tully, T., Quinn, W.G., Classical conditioning and retention in normal and mutant Drosophila melanogaster. J Comp Physiol A. 1985;157:263–277.
39. Feany M., Quinn W. A neuropeptide gene defined by the Drosophila memory mutant amnesiac. Science. 1995;268:869–873.
40. Elkins T, Ganetzky B, Wu C-F. A Drosophila mutation that eliminates a calcium-dependent potassium current. Proc Natl Acad Sci U. S. A. 1986; 83:8415–9.
41. Atkinson NS, Robertson G, Ganetzky B. A component of calcium-activated potassium channels encoded by the Drosophila slo locus. Science 1991;253:551–555.
42. Singh S, Wu, C.-F. Complete separation of four potassium currents in Drosophila. Neuron, 1989;2:1325–1329.
43. Johnson E, Ringo J, Dowse H. Native and heterologous neuropeptides are cardioactive in Drosophila melanogaster. J Insect Physiol. 2000;46:1229–1236.
44. Johnson E, Ringo J, Dowse H. Modulation of Drosophila heartbeat by neurotransmitters. J Comp Physiol B. 1997;167:89–97.
45. Kaplan WD, Trout WE. The behavior of four neurological mutants of Drosophila. Genetics 1969;61:399–409.
46. Warmke J, Drysdale R, Ganetzky B. A distinct potassium channel polypeptide encoded by the Drosophila eag locus. Science 1991;252:1560–1562.
47. Engel JE, Wu C-F. Interactions of membrane excitability mutations affecting potassium and sodium currents in the flight and giant fiber escape systems of Drosophila. J Comp Physiol A. 1992;171:93–104.
48. Brüggemann A, Pardo L, Stühmer W, Pongs O. Ether-à-go-go encodes a voltage-gated channel permeable to K+ and Ca2+ and modulated by cAMP. Nature 1993;365:445–448.
49. Brown H, DiFrancesco D, Noble S. How does adrenaline accelerate the heart? Nature. 1979;280:235-236.
50. Von Schilcher F. The behavior of cacophony, a courtship song mutant in Drosophila melanogaster. Behav Biol. 1976;17:187–96.
51. Smith L, Wang X, et al. A Drosophila calcium channel alpha1 subunit gene maps to a genetic locus associated with behavioral and visual defects. J Neurosci. 1996;16:7868–7879.
52. Smith L, Peixoto A, et al. Courtship and visual defects of cacophony mutants reveal functional complexity of a calcium-channel alpha1 subunit in Drosophila. Genetics. 1998;149:1407–1426.
53. Ray VM, Dowse HB. Mutations in and deletions of the Ca2+ channel-encoding gene cacophony, which affect courtship song in Drosophila, have novel effects on heartbeating. J Neurogenet. 2005;19:39–56.
54. Ashcroft FM. 2000. Ion Channels and Disease. Academic Press.
55. Hille B. Ionic Channels of Excitable Membranes. 3rd ed. Sinauer, Sunderland, editors. Mass. 2001.
56. Olivera BM, Miljanich GP, Ramachandran J, Adams ME. Calcium channel diversity and neurotransmitter release: the omega-conotoxins and omega-agatoxins. Annu Rev Biochem. 1994;63:823–67.
57. Kaplan WD, Trout WE. The behavior of four neurological mu1ts of Drosophila. Genetics. 1969;61:399–409.
58. Warmke JW, Ganetzky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U. S. A. 1994;91:3438–42.
59. Thompson SH. Three pharmacologically distinct potassium channels in molluscan neurones. J Physiol. 1977;265:465–488.
60. Moczydlowski E, Lucchesi K, Ravindran A. 1988. An emerging pharmacology of peptide toxins targeted against potassium channels. J Membr Biol. 1988;105:95–111.
61. Elkins T, Ganetzky B, Wu C-F. A Drosophila mutation that eliminates a calcium-dependent potassium current. Proc Natl Acad Sci U. S. A. 1986;83:8415–9.
62. Fozzard HA. The Heart and cardiovascular system: scientific foundations. Raven Press. 1986.
63. Littleton JT, Ganetzky B. Ion channels and synaptic organization: analysis of the Drosophila genome. Neuron 2000;26:35–43.
64. Lipsius SL, Hüser J, Blatter L. Intracellular Ca2+ release sparks atrial pacemaker activity. News Physiol Sci. 2001;16:101–106.
65. Johnson E, Sherry T, Ringo J Dowse H. 2002. Modulation of the cardiac pacemaker of Drosophila: cellular mechanisms. J Com. Physiol B Biochem Syst Environ Physiol. 2002;172:227–236.
66. Johnson E, Ringo J, Dowse H. Native and heterologous neuropeptides are cardioactive in Drosophila melanogaster. J Insect Physiol. 2000;46:1229-1236.
67. Gagnon A, Kallal L, Benovic. Role of clathrin-mediated endocytosis in agonist-induced downregulation of the β2- adrenergic receptor. J Biol Chem. 1998;273:6976-6981.
68. Grigliatti T, Hall L, et al. Temperature-sensitive mutations in Drosophila melanogaster XIV A selection of immobile adults. Molec Gen Genet. 1973;120:107-114.
69. Chen MS, Obar RA, et al. Multiple forms of dynamin are encoded by shibire, a Drosophila gene involved in endocytosis. Nature, 1991;351:583-586.
70. van der Bliek A, Myerowitz E. Dynamin-like protein encoded by the Drosophila shbire gene associated with vesicular traffic. Nature. 1991;351:411-414.
71. Masur S, Kim Y-T, Wu C-F. REversible lihigibion of endocytosis in cultured neurons from the temperature-sensitive mutation shibirets. J Neurogenet. 1990;6:191-206.
72. Lerner AB, Case JD, Takahashi, et al.. Isolation of melatonin, the pineal gland factor That lightens melanocytes. J Am Chem Soc. 1958;80:2587–2587.
73. McCord CP, Allen FP. Evidences associating pineal gland function with alterations in pigmentation. J. Exp. Zool. 1917;23:207–224.
74. Kitay JI, Altschule MD. The pineal gland: a review of the physiologic literature. Published for the Commonwealth Fund by Harvard University Press 1954.
75. Hardeland R, Cardinali DP, et al. Melatonin--a pleiotropic, orchestrating regulator molecule. Prog Neurobiol. 2011;93:350–84.
76. Man GC-W, Wong JH, et al. Abnormal melatonin receptor 1B expression in osteoblasts from girls with adolescent idiopathic scoliosis. J Pineal Res. 2011;50:395–402.
77. Reiter RJ. Melatonin: the chemical expression of darkness. Mol Cell Endocrinol. 1991;79:C153–8.
78. Yu HS, Hernandez V, Haywood M, Wong CG. Melatonin inhibits the proliferation of retinal pigment epithelial (RPE) cells in vitro. In Vitro Cell Dev Biol Anim. 1993;29A:415–418.
79. Pandi-Perumal SR, Trakht I, et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008;85:335–53.
80. Slominski A, Tobin DJ, et al. Melatonin in the skin: synthesis, metabolism and functions. Trends Endocrinol Metab. 2008;19:17–24.
81. Leja-Szpak A, Jaworek J, et al. Melatonin induces pro-apoptotic signaling pathway in human pancreatic carcinoma cells (PANC-1). J Pineal Res. 2010;49:248–255.
82. Celinski K, Konturek SJ, et al. Melatonin or L-tryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole. J. Pineal Res. 2011;50:389–94.
83. Reppert SM. Melatonin Receptors: Molecular Biology of a New Family of G Protein-Coupled Receptors. J Biol Rhythms 1997;12:528–531.
84. Dubocovich ML, Masana MI, Benloucif S. Molecular pharmacology and function of melatonin receptor subtypes. Adv Exp Med Biol. 1999;460:181–90.
85. Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 2005;27:101–10.
86. Imbesi M, Arslan AD, Yildiz S et al. The melatonin receptor MT1 is required for the differential regulatory actions of melatonin on neuronal “clock” gene expression in striatal neurons in vitro. J Pineal Res. 2009;46:87–94.
87. Shiu SYW, Pang B, Tam CW, Yao K-M. Signal transduction of receptor-mediated antiproliferative action of melatonin on human prostate epithelial cells involves dual activation of Gα(s) and Gα(q) proteins. J Pineal Res. 2010;49:301–11.
88. Reiter RJ. Functional aspects of the pineal hormone melatonin in combating cell and tissue damage induced by free radicals. Eur J Endocrinol. 1996;134:412–20.
89. Tan D, Reiter RJ, Manchester LC, Yan M, et al. 2002. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem. 2002;2:181–97.
90. Silva SO, Rodrigues MR, Ximenes VF, et al. Neutrophils as a specific target for melatonin and kynuramines: effects on cytokine release. J Neuroimmunol. 2004;156:146–52.
91. Mayo JC, Sainz RM, Tan D-X, et al. Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol. 2005;165:139–49.
92. Manda K, Ueno M, Anzai K. AFMK, a melatonin metabolite, attenuates X-ray-induced oxidative damage to DNA, proteins and lipids in mice. J Pineal Res. 2007;42:386–393.
93. Manda K, Ueno M, Anzai K. Space radiation-induced inhibition of neurogenesis in the hippocampal dentate gyrus and memory impairment in mice: ameliorative potential of the melatonin metabolite, AFMK. J Pineal Res. 2008;45:430–8.
94. Hardeland R, Tan D-X, Reiter RJ. Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines. J Pineal Res. 2009;47:109–26.
95. Schaefer M, Hardeland R. The melatonin metabolite N-acetyl-5-methoxykynuramine is a potent singlet oxygen scavenger. J Pineal Res. 2009;46:49–52.
96. Hickman AB, Klein DC, Dyda F. Melatonin Biosynthesis. Mol Cell. 1999;3:23–32.
97. Hintermann E, Jeno P, Meyer U. Isolation and characterization of an arylalkylamine N-acetyltransferase from Drosophila melanogaster. FEBS Lett. 1995;375:148–150.
98. Brodbeck D, Amherd R, Callaerts P. Molecular and biochemical characterization of the aaNAT1 (Dat) locus in Drosophila melanogaster: differential expression of two gene products. DNA Cell Biol. 1998;17:621–33.
99. Amherd R, Hintermann E, Walz D, Affolter M, Meyer U. Purification, cloning, and characterization of a second arylalkylamine N-acetyltransferase from Drosophila melanogaster. DNA Cell Biol. 2000;19:697–705.
100. Hardeland R. Extended Signaling by Melatonin. Cell Cellular Lif Sci J. 2018;3:00123.
101. Padayatty S. et al. Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention. Journal of the American College of Nutrition. 22;1:18-35.
102. Tan DX, Reiter RJ, et al. Ischemia/perfusion induced arrhythmia in the isolated rat heart: prevention my melatonin. J Pineal Res. 1998;25:184-191.
103. Bertuglia S, Reiter RJ. Melatonin reduces ventricular arrhythmias and preserves capillary perfusion during ischemia-reperfusion events in cardiomyopathic hamsters. J Pineal Res. 2007;42:55–63.
104. Diez ER, Prados LV, Carrión A, et al. A novel electrophysiologic effect of melatonin on ischemia/reperfusion-induced arrhythmias in isolated rat hearts. J. Pineal Res. 2009;46:155–160.
105. Benova T, Knezl V, Viczenczova C, et al. Acute anti-fibrillating and defibrillating potential of atorvastatin, melatonin, eicosapentaenoic acid and docosahexaenoic acid demonstrated in isolated heart model. J Physiol Pharmacol. 2015;66:83–89.
106. Goldberger AL. Heartbeat Chaotic or Homestatic? Physiology. 1991;6:87-91.
107. `Lim H-Y, Wang W, et al. ROS Regulate Cardiac Function via a Distinct Paracrine Mechanism. Cell Reports. 2014;7:35-44.
108. Symoens J. Ketanserin: a novel cardiovascular drug. Blood Coagul Fibrinolysis. 1990;1:219-224.
109. Audinot V, Mailliet F, Lahaye-Brasseur C, et al. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn Schmiedebergs Arch Pharmacol. 2003;367:553–561.
110. Bellés X. Beyond Drosophila: RNAi in vivo and functional genomics in insects. Annu Rev Entomol. 2010;55:111–28.
111. Bodmer R. The gene tinman is required for specification of the heart and visceral muscles in Drosophila. Development. 1993;118:719-729.
112. Venkatesh TV, Park M, Ocorr K, et al. Cardiac enhancer activity of the homeobox gene tinman depends on CREB consensus binding sites in Drosophila. Genesis. 2000;13:55-66.
113. Wessells RJ, Bodmer R. Screening assays for heart function mutants in Drosophila. Biotechniques. 2004;37:58–60, 62, 64 passim.
114. Kunwar PS, Starz-Gaiano M, et al. Tre1, a G Protein-coupled receptor, directs transepithelial migration of Drosophila germ cells. PLoS Biol. 2003;1(3):e80.
115. Rezzani R, Rodella LF, Bonomini F, et al. Beneficial effects of melatonin in protecting against cyclosporine A-induced cardiotoxicity are receptor mediated. J Pineal Res. 2006;41:288–95.
116. Yu L, Sun Y, Cheng L, et al. 2014. Melatonin receptor-mediated protection against myocardial ischemia/reperfusion injury: Role of SIRT1. J Pineal Res. 2014;57:228–238.
117. Lochner A. Short and Long Term Effects of Melatonin on Myocardial Post-Ischemic Recovery. J. Pineal Res. 2006;40:56–63.
118. Ding CN1, Cao YX, Zhou L, et al. Effects of microinjection of melatonin and its receptor antagonists into anterior hypothalamic area on blood pressure and heart rate in rats. Acta Pharmacol. 2001;Sin.22:997-1002.
119. Glass L. Introduction to Controversial Topics in Nonlinear Science: Is the Normal Heart Rate Chaotic? Chaos. 2009;19:028501.`
120. Wu G-Q, Arzeno NM, et al. Chaotic Signatures of Heart Rate Variability and Its Power Spectrum in Health, Aging and Heart Failure. PLoS ONE. 2009;4:e4323.
121. Vinogradova T. Rhythmic Ryanodine Receptor Ca2+ releases during diastolic depolarization of sinoatrial pacemaker cells do not require membrane depolarization. Circ Res. 2004;94:802-809.
122. Maltsev V, Lakatta E. Dynamic Interactions of an Intracellular Ca2+ Clock and Membrane Ion Channel Clock Underlie Robust Initiation and Regulation of Cardiac Pacemaker Function. Cardiovascular Res. 2008;77:274-284.
123. Lakatta E, DiFrancesco D. JMCC Point-Counterpoint: What Keeps us Ticking, a Funny Current, a Calcium Clock, or Both? J. Mol. Cell Cardiol. 2009;47:157-170.
124. Lakatta, E. Maltsev V, Vinogradova T. A Coupled SYSTEM of Intracellular Ca2+ Clocks and Surface Membrane Voltage Clocks Controls the Timekeeping Mechanism of the Heart's Pacemaker. Circulation Res. 2010;106:659-673.
125. Wolk R. Arrhythmogenic mechanisms in left ventricular hypertrophy. Europace 2000;2:216–223.
126. Sanyal S, Consoulas C, et al. Analysis of conditional paralytic mutants in Drosophila SERCA reveals novel mechanism for regulating membrane excitability. Genetics. 2005;DOI10.1534.
127. Sanyal, S., T. Jennings, H. Dowse, and M. Ramaswami. Conditional mutations in SERCA, the Sarco-endoplasmic reticulum Ca2+-ATPase, alter heart rate and rhythmicity in Drosophila. J. Comp. Physiol. B. 2005:176: 253-263.
128. Abraham M, Wolf M. Disruption of Sarcoendoplasmic Reticulum Calcium ATPase Function in Drosophila Leads to Cardiac Dysfunction PLoS ONE. 2013;8:e77785.
129. VanKirk T. Effects of melatonin on heartbeat and possible identification of a melatonin receptor in Drosophila melanogaster. Doctoral Thesis University of Maine. 2015.
130. Sullivan, K., Scott, K., Zuker, C., Rubin, G., The ryanodine receptor is essential for larval development in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 2000;97:5492–5497.