丁香园AV

Research Interests:

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:

1. to explore the molecular determinants and biophysical underpinnings of diseases of excitability in cardiac muscle, skeletal muscle, and neurons;
2. to use toxin resistance in sodium channels as a marker for adaptation and parallel evolution;
3. 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.

Recent Publications:

• Diego, J.M., H. Barajas-Martinez, R. Cox, V.M. Robinson, J. Jung, M. Abdelsayed*, M.Fouda*, P.C. Ruben, and C. Antzelevitch, 2023. Mechanisms underlying the antiarrhythmic effect of ARumenamide-787 in experimental models of the J wave syndromes and hypothermia. .
  
• Ghovanloo, M.-R., J. Arnold and P.C. Ruben. 2023. Cannabinoid interactions with ion channels, receptors, and the bio-membrane. 
• Ghovanloo, M.-R., S.D. Dib-Hajj, S.J. Goodchild, P.C. Ruben, and S.G. Waxman. 2022. Non-psychotropic phytocannabinoid interactions with voltage-gated sodium channels: an update on cannabidiol and cannabigerol. 
• Mena Abdelsayed, Dana Page, and Peter C. Ruben. 2022. ARumenamides: A novel class of potential antiarrhythmic compounds.
• Fouda, M.A.*, Y. Fathy-Mohamed, R. Fernandez, and P.C. Ruben. 2022. Anti-inflammatory effects of cannabidiol against lipopolysaccharides in cardiac sodium channels.
• Cannabidiol increases gramicidin current in human embryonic kidney cells: An observational study. 2022. Mohammad-Reza Ghovanloo, Samuel J. Goodchild, Peter C. Ruben.
• Mohamed A. Fouda, Mohammad-Reza Ghovanloo, and Peter C. Ruben. 2022. Late sodium current: incomplete inactivation triggers seizures, myotonias, arrhythmias, and pain syndromes.
• Mohammad-Reza Ghovanloo and Peter C. Ruben. 2021. Cannabidiol and Sodium Channel Pharmacology: General Overview, Mechanism, and Clinical Implications.
• Mohamed A. Fouda and Peter C. Ruben. 2021. Protein Kinases Mediate Anti-Inflammatory Effects of Cannabidiol and Estradiol Against High Glucose in Cardiac Sodium Channels. 
• Ghovanloo, M.-R.*, K. Choudhury, T.S. Bandaru, M.A. Fouda, K. Rayani, R. Rusinova, T. Phaterpekar, K. Nelkenbrecher, A.R. Watkins*, D. Poburko, J. Thewalt, O.S. Andersen, L. Delemotte, S.J. Goodchild, P.C. Ruben. 2021. Cannabidiol inhibits the skeletal muscle Nav1.4 by blocking its pore and by altering membrane elasticity. 
• Sait, L.G., S. Altin, M.-R. Ghovanloo*, D. Hollingworth, P.C. Ruben, and B.A. Wallace. 2020. Cannabidiol interactions with voltage-gated sodium channels. 
• Mohammad-Reza Ghovanloo1, Joseph Atallah, Carolina A. Escudero, and Peter C. Ruben. 2020. Biophysical Characterization of a Novel SCN5A Mutation Associated With an Atypical Phenotype of Atrial and Ventricular Arrhythmias and Sudden Death. 
• 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.
• Cannabidiol protects against high glucose鈥恑nduced oxidative stress and cytotoxicity in cardiac voltage鈥恎ated sodium channels. Mohamed A. Fouda Mohammad鈥怰eza Ghovanloo Peter C. Ruben, 
• Say Cheese: Structure of the Cardiac Electrical Engine Is Captured. Mohammad-Reza Ghovanloo and Peter C. Ruben. Trends in 
• 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 脡ric Samarut. 
• 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. 
• Voltage gated sodium channels in cancer and their potential mechanisms of action. Madeline Angus and Peter C. Ruben 
• 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, B茅atrice Guyomarc鈥檋-Delasalle, Nico A Blom, Yanushi D Wijeyeratne, Jean-Baptiste Gourraud, Herv茅 Le Marec, Junichi Ozawa, V茅ronique Fressart, Jean-Marc Lupoglazoff, Federica Dagradi, Carla Spazzolini, Takeshi Aiba, David J Tester,Laura A Zahavich, Virginie Beaus茅jour-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鈥損henotype correlation and identification of higher-risk subgroups 
• 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. 
• Abdelsayed, M.*, C.H. Peters*, and P.C. Ruben 2018. The efficacy of Ranolazine on E1784K is altered by temperature and calcium. 
• 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. 
• Colin H. PetersMohammad-Reza GhovanlooCynthia GershomePeter C. Ruben 2018. pH Modulation of Voltage-Gated Sodium Channels.  
• Ruben, P.C. 2017. Science is alive and thriving at 丁香园AV. OpEd, November 17, 2017. .
• Abdelsayed, M.*, C.H. Peters*, and P.C. Ruben. 2017. Arrhythmogenic triggers associated with sudden cardiac death. .
• 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. .
• 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. .
• 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. .
• 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. 
• Tarallo-Graovac, M., et al. (including M.Abdelsayed* and P.C. Ruben). Exome Sequencing and the Management of Neuro-metabolic Disorders. 
• Ruben, P.C. and C. Cupples. How academic research leads to innovation.  OpEd, April 11, 2016.
• Ghovanloo, M-R.* and P.C. Ruben. Effects of Amiodarone and N-Desethylamiodarone on Cardiac Voltage-gated Sodium Channels. 2016. 
• 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 鈥渃lassical鈥� congenital myopathy. 
• Peters, C.H.*, M. Abdelsayed*, and P.C. Ruben. 2015. Triggers for Arrhythmogenesis in the Brugada and Long QT 3 Syndromes. .
• 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 I_Na: A Potential Arrhythmogenic Trigger. 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. 
• 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.
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• 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 
• Egri, C.*, Y.Y. Vilin, and P.C. Ruben. 2012. A thermoprotective role of the sodium channel 尾1 subunit is lost with the 尾1(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.