Rash Lab - Ion channel pharmacology

Ion channels are the fastest cellular signalling system in our bodies functioning on the millisecond timescale. They are activated by a wide range of stimuli covering chemical (ligands including changes in pH), electrical (membrane voltage changes) and physical (temperature and stretch) modes. Because of the wide range of triggers and speed with which they transmit signals, ion channels are the “first responders” to changes that occur in a cells environment in both physiological and pathophysiological conditions. Thus, studying how ion channels in different cell types function under these conditions is crucial to understanding the initiation and development of most disease states, as well as identifying novel drug targets.

Given the crucial role of ion channels in normal physiology, many venomous predators (spiders, scorpions, sea anemones, wasps etc.) have evolved libraries of molecules that potently interfere with ion channel function in order to rapidly paralyse prey.  The Ion Channel Pharmacology lab uses animal venoms as well as man-made drugs to help understand the function and modulation of various ion channels in health and disease. We have a particular focus on acid-sensing ion channels and voltage-gated sodium channels and their role in pain, inflammation and neurological disorders such as stroke and spinal cord injury.

The broad research fields of the group cover pharmacology, physiology, biochemistry and toxinology. The expertise and techniques employed include electrophysiology (Xenopus oocytes), high-performance liquid chromatography, mass spectrometry, molecular biology, peptide and protein production & mutagenesis, cell culture/assays, organ bath assays. 

Lab head

Students

  1. Rash LD. (2017) Chapter 3. Acid-sensing ion channel pharmacology, past, present and future... in: Advances in Pharmacology. Volume 79. Ion Channels Downunder. (D.P. Geraghty and L.D. Rash Eds) Elsevier, Amsterdam – in press: doi: 10.1016/bs.apha.2017.02.001.
  2. Wingerd JS, Mozar CA, Ussing CA, Murali SS, Chin YK-Y, Cristofori-Armstrong, Durek T, Gilchrist J, Vaughan CW, Bosmans F, Adams DJ, Lewis RJ, Alewood PF, Mobli M, Christie MJ & Rash LD (2017) The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity. Scientific reports. Accepted March 26, 2017.
  3. Er SY, Cristofori-Armstrong B, Escoubas P & Rash LD (2017) Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1. Neuropharmacology. Accepted Feb 18, 2017. doi: 10.1016/j.neuropharm.2017.03.020
  4. Chassagnon IR, McCarthy CA, Chin YK-Y, Pineda SS, Keramidas A, Mobli M, Lynch JW, Widdop RE, Rash LD^ & King GF^. (2017) Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a. Proceedings of the National Academy of Sciences U. S. A. Accepted Feb 6, 2017. doi: 10.1073/pnas.1614728114
  5. Cristofori-Armstrong B, Soh MS, Talwar S, Brown DL, Griffin JDO, Dekan Z, Stow JL, King GF, Lynch JW & Rash LD. (2015) Xenopus borealis as an alternative source of oocytes for biophysical and pharmacological studies of neuronal ion channels. Scientific Reports. 5. Article # 14763. doi: 10.1038/srep14763
  6. Saez NJ, Deplazes E, Cristofori-Armstrong B, Chassognon IR, Lin X, Mobli M, Mark AE, Rash LD^ & King GF^ (2015) Molecular dynamics and functional studies define a hot spot of crystal contacts essential for PcTx1 inhibition of acid-sensing ion channel 1a. British Journal of Pharmacology. 172(20), 4985-4995. doi10.1111/bph.13267
  7. Chow CY, Cristofori-Armstrong B, Undheim EAB, King GF & Rash LD. (2015) Three peptide modulators of the human voltage-gated sodium channel 1.7, an important analgesic target, from the venom of an Australian tarantula. Toxins, 7, 2494-2513. doi:10.3390/toxins7072494
  8. Simons C#, Rash LD#, Crawford J, Ma L, Cristofori-Armstrong B, Miller D, Ru K, Baillie GJ, Alanay Y, Jacquinet A, Debray F-G, Verloes A, Shen J, Yesil G, Guler S, Yuksel A, Cleary JG, Grimmond SM, McGaughran J, King GF, Gabbett MT & Taft RJ. (2015) Mutations in the voltage- gated potassium channel KCNH1 cause Temple–Baraitser syndrome and non-syndromic epilepsy. Nature Genetics, 41(1), 73-77.  doi: 10.1038/ng.3153
  9. Jensen JE, Cristofori-Armstrong B, Anangi R, Rosengren KJ, Lau CHY, Mobli M, Brust A, Alewood PF, King GF & Rash LD. (2014) Understanding the molecular basis of toxin promiscuity: The analgesic sea anemone peptide APETx2 interacts with ASIC3 and hERG channels via overlapping pharmacophores. Journal of Medicinal Chemistry, 57(21), 9195-9203. doi10.1021/jm501400p
  10. Klint JK, Bereki G, Knapp O, Mobli M, King GF, Adams DJ, Alewood PF & Rash LD. (2014) Isolation, synthesis and characterization of w-TRTX-Cc1a, a novel tarantula venom peptide that selectively targets L-type CaV channels. Biochemical Pharmacology, 89(2), 276-286. doi: 10.1016/j.bcp.2014.02.008
  11. Schroeder C, Rash LD, Vila-Farrés X, Rosengren KJ, Mobli M, King GF, Alewood PF, Craik DJ & Durek T. (2014) Chemical synthesis, 3D structure, and ASIC binding site of the toxin Mambalgin-2. Angewandte Chemie Int. Ed., 53, 1017-1020. doi: 10.1002/anie.201308898
  12. Blanchard MG, Rash LD, Kellenberger S. (2012) Inhibition of voltage-gated Na+ currents in rat DRG neurons by the sea anemone toxin APETx2. British Journal of Pharmacology, 165, 2167-77.  doi: 10.1111/j.1476-5381.2011.01674.x
  13. Salinas M#, Rash LD#, Baron A#, Lambeau G, Escoubas P & Lazdunski M. (2006) The receptor site of the spider toxin PcTx1 on the proton-gated cation channel ASIC1a. Journal of Physiology – London, 570, 339-354. doi: 10.1113/jphysiol.2005.095810
  14. Bosmans F, Rash L, Zhu S, Diochot S, Lazdunski M, Escoubas P & Tytgat T. (2006) Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes. Molecular Pharmacology, 69, 419-429. doi: 10.1124/mol.105.015941
  15. Diochot S, Baron A, Rash L, Deval E, Escoubas P, Scarzello S, Salinas M & Lazdunski M. (2004) A new sea anemone peptide, APETx2, inhibits ASIC3, an important acid-sensitive ionic channel in sensory neurons. EMBO Journal, 23, 1516-1525. doi: 10.1038/sj.emboj.7600177
  16. Rash LD & Hodgson WC. (2002) Pharmacology and biochemistry of spider venoms. Toxicon, 40, 225-254. (review article) doi: 10.1016/S0041-0101(01)00199-4

 

  1. Characterisation of novel sodium channel modulators from spider venoms. 
  2. Spider venom peptides as tools to study acid-sensing ion channels, potential drug targets in neurological disease.  
  3. Ligand-gated ion channels in neurogenic inflammation. The interface between neurons and inflammatory cells. 

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