Axonal ion channels from bench to bedside: A translational neuroscience perspective Arun V. Krishnan a,c , Cindy S.-Y. Lin b,c , Susanna B. Park c , Matthew C. Kiernan c, * a Translational Neuroscience Facility, University of New South Wales, Randwick, Sydney, NSW, Australia b Department of Health and Exercise Science, School of Medical Sciences, University of New South Wales, Randwick, Sydney, NSW, Australia c Prince of Wales Medical Research Institute and Prince of Wales Clinical School, Barker Street, University of New South Wales, Randwick, Sydney, NSW 2031, Australia Contents 1. Introduction ..................................................................................................... 289 2. Saltatory conduction and the axonal membrane ........................................................................ 289 2.1. Axonal Na + channels ......................................................................................... 289 2.1.1. Structure .......................................................................................... 289 2.1.2. Neurotoxins and Na + channel distribution ................................................................ 291 2.1.3. Kinetics of voltage-gated Na + channels .................................................................. 291 2.1.4. Altered Na + channel function and expression in disease ..................................................... 292 2.1.5. Plasticity of Na + channel expression ..................................................................... 292 2.1.6. Drugs targeting Na + channel function ................................................................... 293 2.2. Axonal potassium channels ................................................................................... 293 2.2.1. Fast K v channels..................................................................................... 294 2.2.2. Reorganisation of K v channels in demyelination ........................................................... 294 2.2.3. Slow K v channels .................................................................................... 294 2.2.4. Inwardly rectifying channels ........................................................................... 295 2.2.5. Other axonal K + channels ............................................................................. 295 Progress in Neurobiology 89 (2009) 288–313 ARTICLE INFO Article history: Received 7 May 2009 Received in revised form 17 August 2009 Accepted 17 August 2009 Keywords: Na + /K + pump Axonal excitability Potassium channel Sodium channel Threshold electrotonus ABSTRACT Over recent decades, the development of specialised techniques such as patch clamping and site- directed mutagenesis have established the contribution of neuronal ion channel dysfunction to the pathophysiology of common neurological conditions including epilepsy, multiple sclerosis, spinal cord injury, peripheral neuropathy, episodic ataxia, amyotrophic lateral sclerosis and neuropathic pain. Recently, these insights from in vitro studies have been translated into the clinical realm. In keeping with this progress, novel clinical axonal excitability techniques have been developed to provide information related to the activity of a variety of ion channels, energy-dependent pumps and ion exchange processes activated during impulse conduction in peripheral axons. These non-invasive techniques have been extensively applied to the study of the biophysical properties of human peripheral nerves in vivo and have provided important insights into axonal ion channel function in health and disease. This review will provide a translational perspective, focusing on an overview of the investigational method, the clinical utility in assessing the biophysical basis of ectopic symptom generation in peripheral nerve disease and a review of the major findings of excitability studies in acquired and inherited neurological disease states. Crown Copyright ß 2009 Published by Elsevier Ltd. All rights reserved. Abbreviations: 4-AP, 4-aminopyridine; ADH, activity-dependent hyperpolarization; AED, antiepileptic drugs; AIP, acute intermittent porphyria; ALS, amyotrophic lateral sclerosis; Ba 2+ , barium; Ca 2+ , calcium; CIDP, chronic inflammatory demyelinating polyneuropathy; CIP, channelopathy-associated insensitivity to pain; Cl  , chloride; Cs + , caesium; DN, diabetic neuropathy; ESKD, end-stage kidney disease; GBS, Guillain–Barre ´ syndrome; GEFS+, generalised epilepsy febrile seizures plus; HCO 3  , bicarbonate ion; I H , hyperpolarization-activated current (inwardly rectifying conductance); I/V, current–threshold; K + , potassium; [K + ] o , extracellular potassium concentration; K v , voltage- gated potassium channels; Li 2+ , lithium; MMN, multifocal motor neuropathy; Na + , sodium; Na v , voltage-gated sodium channels; Na + /K + , pump sodium–potassium pump; PE, primary erythermelalgia; PEPD, paroxysmal extreme pain disorder; RRP, relative refractory period; SCI, spinal cord injury; t SD , strength–duration time constant; TEA, tetraethylammonium; TTX, tetrodotoxin. * Corresponding author. Tel.: +61 2 9382 2422; fax: +61 2 9382 2437. E-mail address: M.kiernan@unsw.edu.au (M.C. Kiernan). Contents lists available at ScienceDirect Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio 0301-0082/$ – see front matter . Crown Copyright ß 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2009.08.002