School of Biomedical Sciences

Rash Group - 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. 

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View full list of publications on eSpace

  1. Finol-Urdaneta RK, Ziegman R, Dekan Z, McArthur JR, Heitmann S, Luna-Ramirez K, Tae HS, Mueller A, Starobova H, Chin YKY, Wingerd JS, Undheim EAB, Cristofori-Armstrong B, Hill AP, Herzig V, King GF, Vetter I, Rash LD, Adams DJ, Alewood PF (2022) Multitarget nociceptor sensitization by a promiscuous peptide from the venom of the King Baboon spider. PNAS, 119 (5)

  2. Cristofori-Armstrong B, Budusan E, Rash LD (2021) Mambalgin-3 potentiates human acid-sensing ion channel 1b under mild to moderate acidosis: implications as an analgesic lead. PNAS, 118 (8)

  3. Schendel V, Rash LD, Jenner RA, Undheim EAB (2019) The diversity of venom: the importance of behavior and venom system morphology in understanding its ecology and evolution. Toxins 11 (11), 666

  4. Cristofori-Armstrong B, Saez NS, Chassagnon I, King GF, Rash LD (2019) The modulation of acid-sensing ion channel 1 by PcTx1 is pH-, subtype- and species-dependent: importance of interactions at the channel subunit interface and potential for engineering selective analogues. Biochemical Pharmacology. 163, 381-390.

  5. Lee JYP, Saez NS, Cristofori-Armstrong B, Anangi R, King GF, Smith MT, Rash LD. (2018) Inhibition of acid-sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain. Brit J. Pharmacol. 175 (12), 2204-2218.

  6. 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.
  7. 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.
  8. 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
  9. 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
  10. 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
  11. 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. doi: 10.1111/bph.13267
  12. 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
  13. 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
  14. 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. doi: 10.1021/jm501400p
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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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