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The Role of Sodium Channels in Disease

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MEETING REPORT Highlights of the Society for Medicines Research Symposium held on September 27, 2001, in London. The Role of Sodium Channels in Disease Summary by Alan M. Palmer Native sodium channels exist as polypeptide multimers of an α-subunit (260 kDa) and Nick Carter and subsidiary and smaller β-subunits, which are divided into at least three sub- typesβ1, β2 and β3. The α-subunits are structurally diverse, arising from multiple sodium channel genes and alternative splicing events. Recent progress has led he Society for Medicines to a good understanding of the molecular structure of sodium channels, how they Research symposium The Role work and the significance of their expression in particular cell types. This, coupled T with experimental studies linking particular isoforms with particular disease states of Sodium Channels in Disease was held at the National Heart and and the discovery of distinct human sodium channelopathies (specific mutations Lung Institute of Imperial College of in specific isoforms that cause a variety of diseases, including paralysis, long QT Science, Technology and Medicine on syndrome and epilepsy), is beginning to reveal how particular sodium channel sub- September 27, 2001. The meeting types underlie specific pathologies. All this provides great potential for the devel- focused on the role of sodium channels opment of new therapies. The first generation of sodium channel blockers has led in disease and was organized by Alan to a broad-spectrum anticonvulsant that is now widely used (lamotrigine) and an impressive neuroprotective agent that is in clinical trials for stroke (sipatrigine). The M. Palmer (Vernalis, Wokingham, development of the next generation of sodium channel blockers will be greatly U.K.) and Nick Carter (St. Georges facilitated by elaboration of the pharmacology of the various isoforms, which itself Hospital Medical School, London, is dependent upon the existence of reliable, rapid and high-throughput assays for U.K.), who chaired the proceedings sodium channel activity. © 2001 Prous Science. All rights reserved. together with David Cavalla (Arach- nova, Cambridge, U.K.). The speakers equally represented academia and industry and were from both the tial changes and give rise to character- The pharmacology of sodium United Kingdom and the United istic action potentials. Overactivation channels is currently very rudimenta- States. of sodium channels can lead to neu- ry, since they are distinguished on the ronal dysfunction. Thus, the depolar- basis of sensitivity to a toxin derived Sodium channel activity is intrin- ization of plasma membranes that from puffer fish, tetrodotoxin. It is sic to neurotransmission and, there- occurs in acute brain injury (such as now known that native sodium chan- fore, sodium channels have a central stroke and traumatic brain injury) or nels exist as polypeptide multimers, role in normal neuronal function. overstimulation of certain neurons comprising a large (260 kDa) α-sub- Sodium channels are highly selective (such as that occurring in chronic pain unit and smaller (3336 kDa) modula- molecular pores, the opening and clos- states) leads to excessive sodium tory β-subunits (there are at least three ing of which shape membrane poten- channel activity. different subtypes: β1, β2 and β3). The 568 © 2001 Prous Science CCC: 02140934/2001 Drug News Perspect 14(9), November 2001 TABLE I: MAMMALIAN SODIUM CHANNEL α-SUBUNITS FORMER CHROMOSOMAL SPLICE TYPE NAME GENBANK NO.a GENE SYMBOL LOCATION VARIANTS PRIMARY TISSUES Nav1.1 Rat I X03638 (r) SCN1A Mouse 2 Nav1.1a CNS HBSCI X65362 (h) Human 2q24 PNS GPBI AF003372 (gp) SCN1A Nav1.2 Rat II X03639 (r) SCN2A Mouse 2 Nav1.2a CNS HBSCII X61149 (r) Human 2q23-24 HBA X65361 (h) M94055 (h) Nav1.3 Rat III Y00766 (r) SCN3A Mouse 2 Nav1.3a CNS Human 2q24 Nav1.3b Nav1.4 SkM1, µ-1 M26643 (r) SCN4A Mouse 11 Skeletal muscle M81758 (h) Human 17q23-25 Nav1.5 SkM2 M27902 (r) SCN5A Mouse 9 Uninnervated skeletal muscle, heart H1 M77235 (h) Human 3p21 Nav1.6 NaCh6 L39018 (r) SCN8A Mouse 15 Nav1.6a CNS, PNS PN4 AF049239 (r) Human 12q13 Scn8a AF049240 (r) CerIII U26707 (m) AF049617 (m) AF050736 (h) AF225988 (h) AF003373 (gp) Nav1.7 NaS U35238 (rb) SCN9A Mouse 2 PNS hNE-Na X82835 (h) Human 2q24 Schwann cells PN1 U79568 (r) AF000368 (r) Nav1.8 SNS X92184 (r) SCN10A Mouse 9 DRG PN3 U53833 (r) Human 3p22-24 NaNG Y09108 (m) U60590 (d) Nav1.9 NaN AF059030 (r) SCN11A Mouse 9 Nav1.9a PNS SNS2 AJ237852 (r) Human 3p21-24 PN5 AF118044 (m) NaT AB031389 (m) SCN12A AF126739 (h) AF188679 (h) AF109737 (h) AF150882 (h) Nax Nav2.1 M91556 (h) SCN7A Mouse 2 Heart, uterus, skeletal muscle, astrocytes, DRG Na-G M96578 (r) SCN6Ab Human 2q21-23 SCL11 Y09164 (r) Nav2.3 L36179 (m) aThe letter in parentheses after each accession number indicates the species of origin for the sequence, as follows: h, human; r, rat; rb, rabbit; m, mouse; gp, guinea pig; d, dog. bThis gene was originally assigned symbols SCN6A and SCN7A, which were mapped in human and mouse, respectively. The two most likely represent the same gene, and the SCN6A symbol will probably be deleted. Abbreviations: DRG, dorsal root ganglion; PNS, peripheral nervous system; CNS, central nervous system. Modified from Goldin et al.15 α-subunits are structurally diverse, number of disorders and the elucida- The discovery of compounds that arising from multiple sodium channel tion of distinct sodium channel- block overactivated sodium channels, genes and alternative splicing events opathies, is beginning to reveal how while permitting normal currents of (Table I). Recent progress has led to a particular sodium channel subtypes sodium ions, has provided a basis to good understanding of the molecular are linked to different disease states. develop such sodium channel blockers structure of sodium channels and how All this provides great potential for for the treatment of central nervous they work and the significance of their the development of new therapies system (CNS) disorders, such as expression in particular cell types. and underlines the attractiveness of stroke, traumatic brain injury and pain; This, coupled with the therapeutic util- this underexploited class of com- sodium channel blockers may also ity of sodium channel blockers for a pounds. have utility for other disorders. The Drug News Perspect 14(9), November 2001 569 First generation forward in understanding what might of sodium channel blockers be one of the more general mecha- NH2 The two prototypic sodium chan- nisms was achieved more than two Cl N nel blockers are the phenyltriazine decades ago with the realization that Cl N lamotrigine and the phenylpyrimidine glutamate is not only the main excita- N NH 2 sipatrigine. Both were synthesized tory neurotransmitter in the brain, but Lamotrigine and developed by Wellcome scientists also a powerful neurotoxin to many at Beckenham, U.K. Lamotrigine was different CNS neurons. This work led synthesized as part of a program to dis- to the formulation of the excitotoxic Cl cover new antifolates and was shown hypothesis, wherein excessive gluta- mate receptor activation contributed to NH to have anticonvulsant efficacy. Sipa- 2 trigine arose from a program to devel- (or caused) neuronal cell death. Cl N op analogues of lamotrigine and was Demonstrations that antagonists act- Cl subsequently shown to have neuropro- ing on glutamate receptors of both the N N tective efficacy. At the time, it was NMDA and AMPA subclass were pro- N tective in animal models of stroke and CH3 considered that the efficacy of both Sipatrigine compounds was mediated by inhibi- trauma added weighty evidence in tion of the release of the excitatory support of this hypothesis. The multi- Fig. 1. Prototypic first-generation sodium amino acids aspartate and glutamate. ple failures of this approach in clinical channel blockers. However, John Garthwaite (who trials in stroke victims, however, joined Wellcome as Head of Neuro- necessitate a rethink. It can be argued, science in 1992 and is now at Wolfson with some justification, that the ability of sodium channel-blocking Institute for Biomedical Research, hypothesis was never subjected to drugs to attenuate abnormal activity of University College London, London, proper experimental testing in humans sodium channels without affecting U.K.) reasoned that the mechanism of (e.g., inadequate dosing or too long a normal synaptic transmission proba- action was not defined precisely, since delay prior to drug administration2). bly underlies the good tolerability of both compounds blocked vertadrine- But another factor is that, to a greater sodium channel-blocking drugs. The evoked release but not potassium- or lesser extent, neurodegenerative prototypic example of the first gener- evoked release of excitatory amino disorders affect both neurons in the ation of sodium channel blockers is the acids. The fact that veratrine evokes gray matter and their axons running in broad-spectrum anticonvulsant lamot- release by opening sodium channels the white matter. Moreover, the human rigine (Lamictal; Fig. 1), which is suggested that it was sodium channel brain has disproportionately more now used widely to treat epilepsy. blockade that was underlying the effi- white matter than a rodent brain. Lamotrigine may also have utility in cacy of both lamotrigine and sipatrig- Hence, a better approach has to be one the treatment of other disorders (e.g., ine. This was then demonstrated that is capable of protecting both gray bipolar disorder). Another prototypic directly by electrophysiological stud- and white matter. sodium channel blocker, with a differ- ies of cells expressing recombinant ent efficacy profile, is sipatrigine 1 Nav1.2 sodium channels. Voltage-gated sodium channels are (BW-619C89; Fig. 1), which is expressed at the surface of all neuronal derived chemically from lamotrigine. Prof. Garthwaite went on to elements (dendrites, somata and Sipatrigine is a neuroprotective agent describe how sodium channel blockers axons).
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