B.A. George Washington University
M.S. George Washington University
Ph.D. University of Calgary
Postdoctoral: Hopkins Marine Station, Stanford University
Phone: (778) 782-9351
Fax: (778) 782-3040
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.
- 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. in press, 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.