Communication Between the Plasma Membrane and Cytosolic Cardiac Pacemakers: A Role for Melatonin?
Main Article Content
Abstract
We review here briefly the essentials of the vertebrate cardiac pacemaking system consisting of the populations of ion channels that drive heartbeat. In addition to the sarcolemmal system, there is a second ion channel-based oscillator consisting centrally of a reciprocating Ca2+ flow between the sarcoplasmic reticulum and the cytosol regulated by release through ryanodine receptors and active return by the Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase. We review the considerable similarity between vertebrate and the fly heart pacemakers. In our work with Drosophila, we have shown that melatonin is capable of increasing the rhythmicity of the fly heart to a remarkable level. This is true even in flies bearing mutations that severely damage ion channels central to the plasma membrane pacemaker. We review here evidence showing that mutations in the gene encoding the fly Calcium ATPase have severe effects on heart function. We present further evidence from our work that melatonin has only a modest effect in reversing these defects. We have hypothesized that melatonin acts by altering the relationship between the sarcolemmal and cytosolic oscillators and cite these and previous findings as provocative in this regard.
Article Details
How to Cite
DOWSE, H.; VANKIRK, T..
Communication Between the Plasma Membrane and Cytosolic Cardiac Pacemakers: A Role for Melatonin?.
Medical Research Archives, [S.l.], v. 11, n. 2, feb. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3582>. Date accessed: 16 may 2025.
doi: https://doi.org/10.18103/mra.v11i2.3582.
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. Marian AJ, Asatryan B, Wehrens X. Genetic basis and molecular biology of cardiac arrhythmias in cardiomyopathies. Cardiovascular Research. 2020;116:1600-1619.
2. Goldberger L. Heartbeat Chaotic or Homestatic? Physiology. 1991;6:87-91.
3. 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.
4. Glass L. Introduction to Controversial Topics in Nonlinear Science: Is the Normal Heart Rate Chaotic? Chaos. 2009;19:028501.
5. 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.
6. Diop S, Bodmer R. Drosophila as a model to study the genetic mechansism of obesity-associated heart dysfunction. J Cell Mol Med, 2012;16(5):966-971.
7. Birse RT, 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. Catsch A. Eine erbliche Stӧrung des Bewegungsmechanisms bei Drosophila melanogaster. Z Ind Abstr Vererb. 1944;82:64–66.
9. Kaplan W, Trout W. The behavior of four neurological mutants of Drosophila. Genetics. 1968;61:399–409.
10. Warmke, J., Ganetzky, B., A family of potassium channel genes related to eag in Drosophila and in mammals. Proc Natl Acad Sci. USA. 1994;91:3438–3442.
11. Jackson F, Wilson S, Strichartz G. et al. Two types of mutants affecting voltage-sensitive sodium channels in Drosophila melanogaster. Nature. 1994;308:189–191.
12. Wang X, Reynolds E, Deak P. The seizure locus encodes the Drosophila homolog of the HERG potassium channel. J. Neurosci. 1997;17:882–890.
13. Keating M, Sanguinetti M. Molecular genetic insights into cardiovascular disease. Science 1996;272:681–685.
14. Sanguinetti, M, Curran, M. Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci USA. 1996;93:2208–2212.
15. Curran, M., Splawski I, Timothy K. et al. 1995. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80:795–803.
16. Sanguinetti M., Jiang C, Curran M. et al. 1995. A mechanistic link between an inherited and an ac- quired cardiac arrythmia: HERG encodes the Ikr potassium channel. Cell. 1995;81:299–307.
17. Taghli-Lamallem O, Plantie E, Jagla K. Drosophila in the heart of understanding cardiac diseases: Modeling channelopathies and cardiomyopathies in the fruitfly. J Cardivasc Dev Dis. 2016;3(7):doi:10.3390/jcdd3010007.
18. Irisawa H, Brown H, Giles W. Cardiac pacemaking in the sinoatrial node. Physiol Rev. 1993;73:197–227.
19. Maltsev V, Lakatta E. Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation ad regulation of cardiac pacemaker function. Cardiovascular Research. 2008;77:274-284.
20. Baumgarten C, Fozzard H. 1992. Cardiac resting and pacemaker potentials. In: Fozzard, H.A., et al. (Eds.), The Heart and Cardiovascular System, 2nd edn. New York, Raven Press 1992:963–1001.
21. Hille B. Ion Channels of Excitable Membranes. 2001. Sunderland, MA, Sinauer.
22. Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol. 1988;395:233–253.
23. Gintant G, Cohen I, Dayton B. et al. 1992. Time-dependent outward currents in the heart. In: Fozzard H et al. (Eds.), The Heart and Cardiovascular System, 2nd edn.1992 New York, Raven:1121–1169.
24. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol. 1993;55:455–472.
25. MacDonald E. What keeps us ticking? Sinoatrial node mechano-sensitivity: the grandfather clock of cardiac rhythm. Biophysical Reviews. 2021;13:707-716.
26. 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 Research. 2010;106:659-673.
27. 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(2):157-170.
28. Maltsev V, Lakatta E. Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model. Am J Physiol. 2009;296:H594-H615.
29. 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.
30. Wolk R. Arrhythmogenic mechanisms in left ventricular hypertrophy. Europace 2000;2:216–223.
31. Johnson E, Ringo J, Bray N. et al.. Genetic and pharmacological identification of ion channels central to the Drosophila cardiac pacemaker. J. Neurogenet. 1998;12:1–24.
32. Johnson E, Ringo J, Dowse H. Modulation of Drosophila heartbeat by neurotransmitters. J Comp Physiol B. 1997;167:89–97.
33. Bodmer R, Wessels R, et al. Heart development and function. In: L.I. Gilbert K, Iatrou G. editors Comprehensive Molecular Insect Science. 2005 London Elsevier:199-250.
34. Glass L. Introduction to Controversial Topics in Nonlinear Science: Is the Normal Heart Rate Chaotic? Chaos. 2009;19:028501.
35. Wu G-Q, Arzeno M, Shen L et al. Chaotic Signatures of Heart Rate Variability and Its Power Spectrum in Health, Aging and Heart Failure. PLoS ONE. 2009;4:e4323.
36. Shinbrot T, Grebogi A, Wisdom J. et al. Chaos in a double pendulum. American Journal of Physics. 1992;60:491-500.
37. 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
38. Dowse H. Analyses for physiological and behavioral rhyhmicity. Methods in Enzymology. 2009;454:141-174
39. Kleiger R,Stein P, Bigger,Jr. J. Heart Rate Variability: Measurement and Clinical Utility. A.N.E. 2005;10(1):88–101.
40. Sullivan K., Scott K, et al. The ryanodine receptor is essential for larval development in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 2000;97:5492–5497.
41. Sanyal S, Consoulas H, Kuromi H. et al. Analysis of conditional paralytic mutants in Drosophila sarco-endoplasmic reticulum Calcium ATPase reveals novel mechanisms for regulation of membrane excitability. Genetics. 2005;169:737-750.
42. Sanyal S, Jennings T, Dowse H. et al. Conditional mutations in SERCA, the sarco-endoplalsmic reticulum Ca2+-ATPase, alter heart rate and rhythmicity in Drosophila. J Comp Physiol B. 2005;176:253–263.
43. Abraham M, Wolf M. Disruption of sarcoendoplasmic reticulum calcium ATPase function in Drosophila leads to cardiac dysfunction. PLOS ONE. 2013;8:e77785. https://doi.org/10.1371/journal.pone.0077785
44. VanKirk T. Effects of melatonin on heartbeat and possible identification of a melatonin receptor in Drosophila melanogaster. The University of Maine ProQuest Dissertations Publishing, 2015. 10075122.
2. Goldberger L. Heartbeat Chaotic or Homestatic? Physiology. 1991;6:87-91.
3. 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.
4. Glass L. Introduction to Controversial Topics in Nonlinear Science: Is the Normal Heart Rate Chaotic? Chaos. 2009;19:028501.
5. 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.
6. Diop S, Bodmer R. Drosophila as a model to study the genetic mechansism of obesity-associated heart dysfunction. J Cell Mol Med, 2012;16(5):966-971.
7. Birse RT, 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. Catsch A. Eine erbliche Stӧrung des Bewegungsmechanisms bei Drosophila melanogaster. Z Ind Abstr Vererb. 1944;82:64–66.
9. Kaplan W, Trout W. The behavior of four neurological mutants of Drosophila. Genetics. 1968;61:399–409.
10. Warmke, J., Ganetzky, B., A family of potassium channel genes related to eag in Drosophila and in mammals. Proc Natl Acad Sci. USA. 1994;91:3438–3442.
11. Jackson F, Wilson S, Strichartz G. et al. Two types of mutants affecting voltage-sensitive sodium channels in Drosophila melanogaster. Nature. 1994;308:189–191.
12. Wang X, Reynolds E, Deak P. The seizure locus encodes the Drosophila homolog of the HERG potassium channel. J. Neurosci. 1997;17:882–890.
13. Keating M, Sanguinetti M. Molecular genetic insights into cardiovascular disease. Science 1996;272:681–685.
14. Sanguinetti, M, Curran, M. Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci USA. 1996;93:2208–2212.
15. Curran, M., Splawski I, Timothy K. et al. 1995. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80:795–803.
16. Sanguinetti M., Jiang C, Curran M. et al. 1995. A mechanistic link between an inherited and an ac- quired cardiac arrythmia: HERG encodes the Ikr potassium channel. Cell. 1995;81:299–307.
17. Taghli-Lamallem O, Plantie E, Jagla K. Drosophila in the heart of understanding cardiac diseases: Modeling channelopathies and cardiomyopathies in the fruitfly. J Cardivasc Dev Dis. 2016;3(7):doi:10.3390/jcdd3010007.
18. Irisawa H, Brown H, Giles W. Cardiac pacemaking in the sinoatrial node. Physiol Rev. 1993;73:197–227.
19. Maltsev V, Lakatta E. Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation ad regulation of cardiac pacemaker function. Cardiovascular Research. 2008;77:274-284.
20. Baumgarten C, Fozzard H. 1992. Cardiac resting and pacemaker potentials. In: Fozzard, H.A., et al. (Eds.), The Heart and Cardiovascular System, 2nd edn. New York, Raven Press 1992:963–1001.
21. Hille B. Ion Channels of Excitable Membranes. 2001. Sunderland, MA, Sinauer.
22. Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol. 1988;395:233–253.
23. Gintant G, Cohen I, Dayton B. et al. 1992. Time-dependent outward currents in the heart. In: Fozzard H et al. (Eds.), The Heart and Cardiovascular System, 2nd edn.1992 New York, Raven:1121–1169.
24. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol. 1993;55:455–472.
25. MacDonald E. What keeps us ticking? Sinoatrial node mechano-sensitivity: the grandfather clock of cardiac rhythm. Biophysical Reviews. 2021;13:707-716.
26. 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 Research. 2010;106:659-673.
27. 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(2):157-170.
28. Maltsev V, Lakatta E. Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model. Am J Physiol. 2009;296:H594-H615.
29. 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.
30. Wolk R. Arrhythmogenic mechanisms in left ventricular hypertrophy. Europace 2000;2:216–223.
31. Johnson E, Ringo J, Bray N. et al.. Genetic and pharmacological identification of ion channels central to the Drosophila cardiac pacemaker. J. Neurogenet. 1998;12:1–24.
32. Johnson E, Ringo J, Dowse H. Modulation of Drosophila heartbeat by neurotransmitters. J Comp Physiol B. 1997;167:89–97.
33. Bodmer R, Wessels R, et al. Heart development and function. In: L.I. Gilbert K, Iatrou G. editors Comprehensive Molecular Insect Science. 2005 London Elsevier:199-250.
34. Glass L. Introduction to Controversial Topics in Nonlinear Science: Is the Normal Heart Rate Chaotic? Chaos. 2009;19:028501.
35. Wu G-Q, Arzeno M, Shen L et al. Chaotic Signatures of Heart Rate Variability and Its Power Spectrum in Health, Aging and Heart Failure. PLoS ONE. 2009;4:e4323.
36. Shinbrot T, Grebogi A, Wisdom J. et al. Chaos in a double pendulum. American Journal of Physics. 1992;60:491-500.
37. 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
38. Dowse H. Analyses for physiological and behavioral rhyhmicity. Methods in Enzymology. 2009;454:141-174
39. Kleiger R,Stein P, Bigger,Jr. J. Heart Rate Variability: Measurement and Clinical Utility. A.N.E. 2005;10(1):88–101.
40. Sullivan K., Scott K, et al. The ryanodine receptor is essential for larval development in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 2000;97:5492–5497.
41. Sanyal S, Consoulas H, Kuromi H. et al. Analysis of conditional paralytic mutants in Drosophila sarco-endoplasmic reticulum Calcium ATPase reveals novel mechanisms for regulation of membrane excitability. Genetics. 2005;169:737-750.
42. Sanyal S, Jennings T, Dowse H. et al. Conditional mutations in SERCA, the sarco-endoplalsmic reticulum Ca2+-ATPase, alter heart rate and rhythmicity in Drosophila. J Comp Physiol B. 2005;176:253–263.
43. Abraham M, Wolf M. Disruption of sarcoendoplasmic reticulum calcium ATPase function in Drosophila leads to cardiac dysfunction. PLOS ONE. 2013;8:e77785. https://doi.org/10.1371/journal.pone.0077785
44. VanKirk T. Effects of melatonin on heartbeat and possible identification of a melatonin receptor in Drosophila melanogaster. The University of Maine ProQuest Dissertations Publishing, 2015. 10075122.