B.A. George Washington University
M.S. George Washington University
Ph.D. University of Calgary
Postdoctoral: Hopkins Marine Station, Stanford University
Positions: Professor, Department of Biomedical Physiology and Kinesiology, SFU
Associate Member of the Department of Molecular Biology and Biochemistry, SFU
Associate Member of the Department of Biological Sciences, SFU
Associate Member of the Department of Cell and Physiological Science, UBC
Molecular Cardiac Physiology Group
The long-term goals of our research are to assess the biophysical sequelae of identifiable sodium channel mutations and substitutions that lead to changes in cellular excitability and toxin resistance.
The sodium channel is a crucial component in electrically excitable cells throughout the animal kingdom and constitutes the primary basis on which electrical impulses are founded in nerve and muscle cells. Its function requires an exquisite balance between its various gating properties as well as its ion selectivity. These properties are based on a sequence of amino acids that imparts voltage-sensitive mobility and sodium ion selectivity to the molecule's ornate structure. Both the complexity and importance of the sodium channel has made it an ideal target for toxins, medicinal and recreational drugs, and the molecular basis of heritable neurological, muscular, and cardiovascular disease states. Using a unification of molecular and biophysical approaches, our research leads to a more complete understanding of the structure-function relationships within the sodium channel molecule. In so doing, we relate channel availability to a variety of disease states including idiopathic ventricular fibrillation, epilepsy, nondystrophic myotonia, and periodic paralysis, and the pharmacological alleviation of these conditions.
The general aims of our research are to explore the biophysical properties of sodium channels that regulate their availability. We have discovered that sodium channel availability, and thus cell excitability, is most heavily dependent on steady-state inactivation, a phenomenological process that is comprised of the physical states of fast and slow inactivation. Although fast inactivation has been well defined, slow inactivation is still an elusive process and thus forms a primary target of my laboratory's work. Recently, we have discovered that defects in deactivation are a consistent theme underlying non-dystrophic myotonia.
The specific experimental aims of our research are:
- to explore the molecular determinants and biophysical underpinnings of diseases of excitability in cardiac muscle, skeletal muscle, and neurons;
- to use toxin resistance in sodium channels as a marker for adaptation and parallel evolution;
- to determine the interactions between activation, deactivation, fast inactivation and slow inactivation in the regulation of sodium channel availability and the contribution of sodium channels to cell excitability, the responsiveness of cells to excitatory synaptic input, and the production of action potentials.
In pursuit of these goals, we use PCR-based site-directed mutagenesis, heterologous expression in Xenopus oocytes and HEK293 cells, patch clamp electrophysiology to measure ionic currents, cut-open oocyte electrophysiology to measure ionic and gating currents, and site-directed fluorescence labeling to measure molecular movements.
E1784K, the most common Brugada syndrome and long-QT syndrome type 3 mutant, disrupts sodium channel inactivation through two separate mechanisms. 2020. Colin H. Peters, Abeline R. Watkins, Olivia L. Poirier, Peter C. Ruben. Journal of General Physiology 152 (9): e202012595
- Cannabidiol protects against high glucose‐induced oxidative stress and cytotoxicity in cardiac voltage‐gated sodium channels. Mohamed A. Fouda Mohammad‐Reza Ghovanloo Peter C. Ruben, British Journal of Pharmacology. 19 February 2020.
- Say Cheese: Structure of the Cardiac Electrical Engine Is Captured. Mohammad-Reza Ghovanloo and Peter C. Ruben. Trends in Biochemical Sciences. 24 February 2020.
- Functional Genomics of Epilepsy and Associated Neurodevelopmental Disorders Using Simple Animal Models: From Genes, Molecules to Brain Networks. Richard Rosch, Dominic R. W. Burrows, Laura B. Jones, Colin H. Peters, Peter Ruben and Éric Samarut. Frontiers in Cellular Neuroscience
- A Novel Amino Acid Duplication in the N-terminus of the Brain Sodium Channel NaV1.1 Underlying Dravet Syndrome Madeline Angus, Colin H Peters, Damon Poburko, Elise Brimble, Emily M Spelbrink, and Peter C. Ruben. Journal of Neurophysiology
- Voltage gated sodium channels in cancer and their potential mechanisms of action. Madeline Angus and Peter C. Ruben Channels
- Alban-Elouen Baruteau, Florence Kyndt, Elijah R Behr, Arja S Vink, Matthias LachaudAnna Joong, Jean-Jacques Schott, Minoru Horie, Isabelle Denjoy, Lia Crotti, Wataru Shimizu, Johan M Bos, Elizabeth A Stephenson, Leonie Wong, Dominic J Abrams, Andrew M Davis, Annika Winbo, Anne M Dubin, Shubhayan Sanatani, Leonardo Liberman, Juan Pablo, Kaski Boris Rudic, Sit Yee Kwok, Claudine Rieubland, Jacob Tfelt-Hansen, George F Van Hare, Béatrice Guyomarc’h-Delasalle, Nico A Blom, Yanushi D Wijeyeratne, Jean-Baptiste Gourraud, Hervé Le Marec, Junichi Ozawa, Véronique Fressart, Jean-Marc Lupoglazoff, Federica Dagradi, Carla Spazzolini, Takeshi Aiba, David J Tester,Laura A Zahavich, Virginie Beauséjour-Ladouceur, Mangesh Jadhav, Jonathan R Skinner, Sonia Franciosi, Andrew D Krahn, Mena Abdelsayed, Peter C Ruben, Tak-Cheung Yung, Michael J Ackerman, Arthur A Wilde, Peter J Schwartz, and Vincent Probst. SCN5A mutations in 442 neonates and children: genotype–phenotype correlation and identification of higher-risk subgroups European Heart Journal, Volume 39, Issue 31, 14 August 2018, Pages 2879–2887
- Mohammad-Reza Ghovanloo,Noah Gregory Shuart, Janette Mezeyova, Richard A. Dean, Peter C. Ruben and Samuel J. Goodchild. 2018. Inhibitory effects of cannabidiol on voltage-dependent sodium currents. Journal of Biological Chemistry
- Abdelsayed, M.*, C.H. Peters*, and P.C. Ruben 2018. The efficacy of Ranolazine on E1784K is altered by temperature and calcium. Scientific Reports volume 8
- Mohammad-Reza Ghovanloo, Mena Abdelsayed, Colin H. Peters & Peter C. Ruben 2018. A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels. Scientific Reports volume 8
- Colin H. PetersMohammad-Reza GhovanlooCynthia GershomePeter C. Ruben 2018. pH Modulation of Voltage-Gated Sodium Channels. HEP, volume 246
- Ruben, P.C. 2017. Science is alive and thriving at Simon Fraser University. OpEd, November 17, 2017. Vancouver Sun.
- Abdelsayed, M.*, C.H. Peters*, and P.C. Ruben. 2017. Arrhythmogenic triggers associated with sudden cardiac death. Channels.
- Peters, C.H.*, Yu, A.*, Zhu, W., Silva, J.R., and P.C. Ruben. 2017. Depolarization of the conductance-voltage relationship in the NaV1.5 mutant, E1784K, is due to altered fast inactivation. PLOS One.
- Thibodeau, M., et al (including C.H. Peters*, C. Gershome*, and P.C. Ruben). 2017. Compound heterozygous TRPV4 mutations in two siblings with a complex phenotype including severe intellectual disability and neuropathy. American Journal of Medical Genetics.
- Abdelsayed, M.*, A.E. Baruteau, K. Gibbs, A. Krahn, S. Sanatani, and P.C. Ruben. 2017. Altered calcium sensitivity in SCN5a E1784K, a mixed syndrome mutant, correlates with LQTS during exercise. Journal of Physiology.
- C. Peters, R.E. Rosch, E. Hughes, and P.C. Ruben. 2016. Temperature-dependent changes in neuronal dynamics in a patient with an SCN1A mutation and hyperthermia induced seizures. Scientific Reports 6, Article number 31879.
- Tarallo-Graovac, M., et al. (including M.Abdelsayed* and P.C. Ruben). Exome Sequencing and the Management of Neuro-metabolic Disorders. New England Journal of Medicine.
- Ruben, P.C. and C. Cupples. How academic research leads to innovation. Vancouver Sun OpEd, April 11, 2016.
- Ghovanloo, M-R.* and P.C. Ruben. Effects of Amiodarone and N-Desethylamiodarone on Cardiac Voltage-gated Sodium Channels. 2016. Frontiers in Pharmacology
- Aimar, K.*, M-R. Ghovanloo*, R.G. Tavi, A. Yu*, and P.C. Ruben. Physiology and pathophysiology of sodium channel inactivation. In press, Sodium Channels Across Phyla and Function in Current Topics in Membranes.
- Zaharieva, I., et al. (including M. Abdelsayed* and P.C. Ruben). 2015. Loss of function mutations in SCN4A result in severe foetal hypokinesia or “classical” congenital myopathy. Brain
- Peters, C.H.*, M. Abdelsayed*, and P.C. Ruben. 2015. Triggers for Arrhythmogenesis in the Brugada and Long QT 3 Syndromes. Progress in Biophysics and Molecular Biology.
- Abdelsayed, M.*, C.H. Peters*, and P.C. Ruben. 2015. Differential thermosensitivity in mixed syndrome mutants in NaV1.5. Journal of Physiology 593(18):4201-4223.
- Jones, D.K.* and P.C. Ruben. 2014. Proton Modulation of Cardiac INa: A Potential Arrhythmogenic Trigger. Handbook of Experimental Pharmacology 221.
- Peters, C.H.* and P.C. Ruben. 2014. Introduction to sodium channels. Handbook of Experimental Pharmacology 221.
- Ruben, P.C. 2014. Editor, Handbook of Experimental Pharmacology 221.
- Abdelsayed, M.*, S. Sokolov, and P.C. Ruben. 2013. A thermosensitive mutation alters the effects of lacosamide on slow inactivation in neuronal voltage-gated sodium channels, NaV1.2. Frontiers in Pharmacology.
- Jones, D.K.*, T.W. Claydon, and P.C. Ruben. 2013. Extracellular protons inhibit charge immobilization in the cardiac voltage-gated sodium channel. Biophysical Journal 105(1):101-107.
- Sokolov, S., C.H. Peters*, S.Rajamani, and P.C. Ruben. 2013. Proton-dependent inhibition of the cardiac sodium channel, NaV1.5, by ranolazine. Frontiers in Pharmacology 4:78.
- Peters, C.H.*, S. Sokolov, S. Rajamani, and P.C. Ruben. 2013. Effects of the antianginal drug, Ranolazine, on the brain sodium channel NaV1.2 and its modulation by extracellular protons. British Journal of Pharmacology 169(3):704-716.
- Jones, D.K.*, C.H. Peters*, C.R. Allard, T.W. Claydon, and P.C. Ruben. 2013. Proton sensors in the pore domain of the cardiac voltage-gated sodium channel. Journal of Biological Chemistry. 288:4782-4791.
- Vilin, Y.Y., C.H. Peters*, and P.C. Ruben. 2012. Acidosis differentially modulates inactivation in NaV1.2, NaV1.4, and NaV1.5 channels. Frontiers in Pharmacology 3(109):1-21.
- Egri, C. and P.C. Ruben. 2012. A Hot Topic: Temperature Sensitive Sodium Channelopathies. Channels, 6(2):75-85.
- Egri, C. and P.C. Ruben. 2012 Action Potentials: Generation and Propagation. In: eLS 2012, John Wiley & Sons, Ltd: Chichester http://www.els.net/
- Egri, C.*, Y.Y. Vilin, and P.C. Ruben. 2012. A thermoprotective role of the sodium channel β1 subunit is lost with the β1(C121W) mutation. Epilepsia, 53:494-505.
- Jones, D.K.*, C.H. Peters*, S.A. Tolhurst*, T.W. Claydon, and P.C. Ruben. 2011. Extracellular proton modulation of the cardiac voltage-gated sodium channel, NaV1.5. Biophys. J. 101:2147-2156.
- Lee, C.H.*, D.K. Jones*, C. Ahern, M.F. Sarhan, and P.C. Ruben. 2011. Biophysical costs associated with tetrodotoxin resistance in the sodium channel pore of the garter snake, Thamnophis sirtalis. Journal of Comparative Physiology A. 197(1) 33-43.
- Lee, C.H.* and P.C. Ruben. 2008. Interaction between voltage-gated sodium channels and the neurotoxin, tetrodotoxin. Channels 2(6):407-413.
- Sun H, Varela D, Chartier D, Ruben PC, Nattel S, Zamponi GW, Leblanc N. Differential interactions of Na+ channel toxins with T-type Ca2+ channels. J Gen Physiol. 2008 Jul;132(1):101-13.
- D.K. Jones and P.C. Ruben Biophysical defects in voltage-gated sodium channels associated with Long QT and Brugada syndromes Volume: 2 | Issue: 2 | Pages: 70 - 80
- Kole, M.H.P., S.U. Ilschner, B.M. Kampa, S.R. Williams, P.C. Ruben, and G.J. Stuart. 2008. Action potential generation requires a high axon initial segment sodium channel density maintained by anchoring to the actin cytoskeleton. Nature Neuroscience 11(2):178-186.
- Groome, J.R., M.S. Dice, E. Fujimoto, and P.C. Ruben. 2007. Charge immobilization of skeletal muscle sodium channels: role of residues in the inactivation linker. Biophysical Journal. 93:1519-1533.
- Dice, M.S., T. Kearl and P.C. Ruben. 2006. Methods for studying voltage-gated sodium channels in heterologous expression systems. in Methods in Molecular Medicine: Cardiovascular Disease. Volume 2, Chapter 11, pp 163-185. ed. Qing Wang. Humana Press, New Jersey, USA.
- Geffeney, S.L. and P.C. Ruben. 2006. The structural basis and functional consequences of interactions between tetrodotoxin and voltage-gated sodium channels. Marine Drugs 4: 143-156.
- Salvador-Recatala, V., W.J. Gallin, J. Abbruzzese, P.C. Ruben and A.N. Spencer. 2006. A potassium channel (Kv4) cloned from the heart of the tunicate Ciona intestinalis and its modulation by a KChIP subunit. Journal of Experimental Biology 209:731-747.200
- Groome, J.R., E. Fujimoto and P.C. Ruben. 2005. K-aggravated myotonia mutations at residue G1306 differentially alter deactivation gating of human skeletal muscle sodium channels. Cellular and Molecular Neurobiology 25:1075-1092.
- Geffeney, S.L., E. Fujimoto, E.D. Brodie, III, E.D. Brodie, Jr., and P.C. Ruben. 2005. Evolutionary diversification of TTX-resistant sodium channels in a predator-prey interaction. Nature 434:759-763.
- Dice, M., J. Abbruzzese, J. Wheeler, J. Groome, E. Fujimoto and P.C. Ruben. 2004. Temperature-sensitive defects in paramyotonia congenita mutants R1448C and T1313M. Muscle and Nerve 30:277-288.
- Locher C.P., P.C. Ruben, J. Gut, P.J. Rosenthal. 2003. 5HT1A Serotonin receptor agonists inhibit Plasmodium falciparum by blocking a membrane channel. Antimicrobial Agents and Chemotherapy 47:3806-3809.
- McCollum, I.A., Y.Y. Vilin, E. Spackman, E. Fujimoto and P.C. Ruben. 2003. Negatively charged residues adjacent to IFM motif in the DIII-DIV linker of hNaV1.4 differentially affect slow inactivation. FEBS Letters 552:163-169.
- Groome, J.R., E. Fujimoto and P.C. Ruben. 2003. Charged residues in the DIII-IV linker regulate deactivation in voltage-gated sodium channels. Journal of Physiology 548:85-96.
- Geffeney, S., E.D. Brodie, Jr., P.C. Ruben and E.D. Brodie, III. 2002. Mechanisms of adaptation in a predator-prey arms race: TTX-resistant sodium channels. Science 297: 1336-1339.
- Groome, J.R., E. Fujimoto, L. Walter and P.C. Ruben. 2002. Charged residues in DIVS4 of skeletal muscle sodium channels have differing roles in deactivation. Biophysical Journal 83:1293-1307.
- Vilin, Y.Y. and P.C. Ruben. 2001. Slow inactivation of sodium channels: Mechanisms, interactions and associations with channelopathies. Cell Biochemistry and Biophysics 35:171-190.
- Vilin, Y., E. Fujimoto and P.C. Ruben. 2001. A single residue differentiates between cardiac and skeletal muscle sodium channel slow inactivation. Biophysical Journal 80:2221-2230.
- Vilin, Y.Y., E. Fujimoto and P.C. Ruben. 2001. A novel mechanism associated with idiopathic ventricular fibrillation (IVF) mutations R1232W and T1620M in human cardiac sodium channels. Pflüegers Archives 402:204-211.