个人简介

B.A. George Washington University M.S. George Washington University Ph.D. University of Calgary Postdoctoral: Hopkins Marine Station, Stanford University

研究领域

Biophysics of ion channels, congenital heart disease, congenital epilepsy, congenital skeletal muscle disease, ion channel evolution

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.

近期论文

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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.