Regulation of Na v channels in sensory neurons Mohamed Chahine 1 , Rahima Ziane 1 , Kausalia Vijayaragavan 1 and Yasushi Okamura 2 1 Laval Hospital, Research Centre, Sainte-Foy, Quebec G1V 4G5, Canada, and Department of Medicine, Laval University, Sainte-Foy, Quebec G1K 7P4, Canada 2 Department of Developmental Neurophysiology, Okazaki Institute for Integrative Bioscience, Okazaki, Japan Voltage-gated Na C channels have an essential role in the biophysical properties of nociceptive neurons. Factors that regulate Na C channel function are of interest from both pathophysiological and therapeutic perspectives. Increasing evidence indicates that changes in expression or inappropriate modulation of these channels leads to electrical instability of the cell membrane and the inappropriate spontaneous activity that is observed following nerve injury, and that this might contribute to neuropathic pain. The role of Na v channels in nociception depends on modulation by factors such as auxiliary b-subunits, cytoskeletal pro- teins and the phosphorylation state of neurons. In this review we describe the modulation of Na v channels on sensory neurons by auxiliary b-subunits, protein kinases and cytoskeletal proteins. Physiology and molecular biology of Na C channels Voltage-gated Na C channels transmit electrical signals through action-potential (AP) generation and propagation from sensory neurons to the CNS. They have important roles in modulating the resting membrane potential and subthreshold oscillations, and in the generation and conduction of APs. Sensory neurons express several Na C channel iso- forms. The situation is made more complex because these channels complex with one or more auxiliary b-subunits to create further diversity in the behaviour of these Na C channels and, thus, the physiology of the specific neuron. In addition to the heterogeneity caused by association with auxiliary b-subunits, Na C channels are also modu- lated by isoforms of protein kinase C (PKC) and PKA, G proteins, receptors, cytoskeletal elements, and adaptor proteins such as ankyrins. Initial influx of Na C causes subthreshold depolariz- ation of the membrane through a rapid, transient increase in Na C conductance to a level that equals the K C conductance (which is responsible for the resting mem- brane potential). Subthreshold responses vary in sensory neurons but seem to be modulated by the presence of persistent currents in C-fibres [1]. AP thresholds also differ: C-fibres have a high voltage threshold for AP activation (41G5 mV), whereas A-fibres have a lower threshold (30G4 mV), probably because of differences in the Na C channel isoforms and their densities in these neurons. Aa/b- and Ad-fibres conduct predominantly low- threshold, fast-inactivating, tetrodotoxin-sensitive (TTX-S) currents that contribute to the AP with a rising time of 200–300 dV dt K1 , whereas C-fibres conduct high- threshold, slow-inactivating, TTX-resistant (TTX-R) cur- rents that contribute to the AP with a rising time of 170 dV dt K1 [2]. Ten isoforms of voltage-gated Na C chan- nels have been cloned from various tissues [3]; these channels differ in primary structure, and pharmacological and biophysical properties (Table 1). Voltage-gated Na C channels are heteromultimeric complexes that are com- posed of one 260-kDa a-subunit and either one or more auxiliary b-subunits (b 1 –b 4 )(Figure 1). The isoforms of the a-subunits are classified as either sensitive or insensitive to TTX. To date, at least seven of the mammalian Table 1. Diversity and properties of Na v channels a Channel name Gene name Human chromosome location TTX sensitivity Tissue localization Expression in sensory neurons b Na v 1.1 SCN1A 2q2a Sensitive CNS, PNS, heart CCC Na v 1.2 SCN2A 2q23–24 Sensitive CNS C Na v 1.3 SCN3A 2q24 Sensitive CNS, heart Expression after axotomy Na v 1.4 SCN4A 17q23–25 Sensitive Skeletal muscle – Na v 1.5 SCN5A 3p21 Resistant Heart, CNS – Na v 1.6 SCN8A 12q13 Sensitive CNS, PNS, heart, glia, nodes of Ranvier CCC Na v 1.7 SCN9A 2q24 Sensitive PNS, Schwann cells CCC Na v 1.8 SCN10A 3p22–24 Resistant PNS CCC Na v 1.9 SCN11A 3p21–24 Resistant PNS CCC a Reviewed in [3]. b CCC, abundant; C, present; –, no expression. Corresponding author: Chahine, M. (mohamed.chahine@phc.ulaval.ca). Available online 25 August 2005 Review TRENDS in Pharmacological Sciences Vol.26 No.10 October 2005 www.sciencedirect.com 0165-6147/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2005.08.002