Elsevier

Drug Discovery Today

Volume 5, Issue 11, 1 November 2000, Pages 506-520
Drug Discovery Today

Review
Voltage-gated sodium channels as therapeutic targets

https://doi.org/10.1016/S1359-6446(00)01570-1Get rights and content

Abstract

Voltage-gated sodium channels (VGSCs) play a central role in the generation and propagation of action potentials in neurons and other cells. VGSC modulators have their origins in empirical pharmacology and are being used as local anaesthetics, antiarrhythmics, analgesics and antiepileptics, and for other disorders. However, the identification of a multigene family of VGSCs, along with tools to study the different subtypes in pathophysiology, is now providing a rational basis for selective intervention. Recent advances have addressed the technical challenges of expressing and assaying these complex proteins, enabling the correlation of empirical pharmacology to subtypes and the screening of individual subtypes for novel inhibitors with increased potency and selectivity.

Section snippets

Multiple channel states and drug action

The current understanding of VGSC function is based on fundamental biophysical studies that distinguished at least three functional states: (1) open, (2) resting and (3) inactivated. At normal membrane potentials, channels are in a closed, resting state. Membrane depolarization activates channels to the open state allowing the rapid influx of sodium ions. During prolonged depolarization (>1 ms), the channels inactivate and sodium influx declines; in this state, the channels remain closed and

Functional domains of VGSC polypeptides

Purification of the VGSC revealed it to be a multisubunit complex consisting of a highly glycosylated pore-forming a subunit (260 kDa), with one or two accessory β subunits1 (33–36 kDa); a third b subunit isoform has also recently been discovered2. Cloning and sequence analysis of VGSC α-subunit cDNAs predicts structural features in common with the large superfamily of voltage-gated ion channels, including potassium and calcium channels (Fig. 1). Channels of this type are all formed by the

Toxin and drug binding sites

A variety of toxins that modulate VGSCs have been used as tools to probe channel function. They can be classified on the basis of five discrete binding sites (Table 2) and these are beginning to be characterized at the molecular level. VGSCs are often subdivided on the basis of their sensitivity to TTX, the lethal component of puffer fish. A single residue (Cys374 in the cardiac channel or Ser356 in SNS) is critical for TTX resistance7., 8.. The binding site for batrachotoxin (BTX), an alkaloid

Molecular and functional diversity of VGSCs

Molecular cloning has uncovered a surprising diversity of VGSCs. To date, at least 10 a subunits (Table 3) have been identified, which are highly conserved across different mammalian species. The potential for functional diversity is further increased by alternative mRNA splicing, modulation by cellular factors and assembly with different b subunits. Understanding the consequences of such diversity and elucidating the precise physiological roles of the different variants remain important

Modulation by b subunits, phosphorylation and G proteins

Three accessory β subunits (β1, β2 and β3) modulate the activity of a subunits and hence provide yet more potential for channel diversity. They are non-essential for core channel function and indeed are absent from the Drosophila genome. Co-expression of β1 and β2 with a subunits accelerates channel gating to physiological rates, alters the voltage dependence of inactivation and increases peak currents. The magnitude of these effects varies with different a subtypes and with the expression

Origins of VGSC pharmacology

The empirical origins of VGSC drugs arose in two areas: (1) local anaesthetics, leading to antiarrhythmics, and (2) anti-epileptic drugs. In 1905, following a search for alternatives to cocaine, several synthetic amino-benzoates that had local anaesthetic properties were discovered, for example, procaine. This is hydrolysed rapidly in vivo and an attempt to find a superior drug led to the stable analogue lignocaine (called lidocaine in the USA). It was not until 1959 that these compounds were

Cardiovascular indications

Antiarrythmic compounds have been categorized by their effects on the fast sodium current (class I), sympathetic activity of the heart (class II), repolarization currents (class III) and slow inward calcium current (class IV). Class I antiarrythmics act by decreasing the rapid phase of depolarization (phase 0) in conduction and myocardial fibres. Class I antiarrythmics such as lignocaine, tocainide and mexiletine exert a well-documented voltage and frequency-dependent block of cardiac sodium

Epilepsy

Epileptic seizures are characterized by high-frequency trains of action potentials, resulting in repetitive synchronized burst firing of neuronal populations in the brain. Such seizures are broadly categorized as either partial or generalized. Partial seizures originate from a specific brain region, for example, the cerebral cortex, whereas generalized seizures involve both brain hemispheres. Generalized seizures can be further subdivided into clonic, myoclonic, tonic, tonic-clonic (grand mal)

Pain

Pain can be broadly subdivided into three categories: (1) nociceptive (including acute surgical pain), (2) neuropathic and (3) inflammatory. Recently, most attention has focussed on the role of VGSCs in neuropathic pain, perhaps because of the largely unmet need39, although further opportunities for therapeutic intervention do exist in each of the pain areas.

Local anaesthetics have a unique profile in pain treatment, from topical application to produce cutaneous anaesthesia, through to spinal

Stroke

Ischaemic damage such as stroke or other brain injuries results in delayed neuronal damage in the brain. Although there is currently no effective therapy, interest in VGSC drugs is considerable. VGSC inhibitors of relatively low potency and selectivity have been shown to prevent neuronal cell death in animal models of cerebral ischaemia, probably because of their modulation of glutamate release and neuroprotection during periods of energy depletion44. In the rat model of focal ischaemia,

Bipolar depression

Bipolar disorder is a complex disease characterized by recurrent episodes of depression together with one or more episodes of mania. Data from six independent clinical studies, including a Phase III trial51, over the past four years demonstrate that lamotrigine is an effective treatment. The most recent study was carried out in 324 patients who met specific criteria for rapid cycling bipolar disorder; more than 40% of the patients taking lamotrigine responded to treatment. Improvements were

Hereditary muscle diseases

Genetic analysis has shown the hereditary muscle dis-orders hyperkalemic periodic paralysis, type II (Hyper PP), potassium aggravated myotonia (PAM) and paramyotonia congentia (PC) to be tightly linked to the human skeletal muscle VGSC on chromosome 17 (Ref. 53). Patients with these disorders show episodic loss of excitability of skeletal muscle. Across these three disorders, 16 disease-causing amino acid changes have been identified (Fig. 5). A variety of these channel mutants have been

Other diseases

Marketed inhibitors of VGSCs continue to be evaluated in conditions such as Parkinson's disease, schizo-affective disorder, tinnitus, migraine and substance abuse, although the multiple actions of these drugs often makes it difficult to clearly associate any clinical benefits with inhibition of VGSCs55.

Assay technology and target-driven drug discovery

Target-driven drug discovery is still in its infancy for VGSCs, similar to other voltage-gated ion channels. The technical issues that have inhibited it are: (1) stable expression of VGSCs and (2) robust high-throughput assays.

Cloning, manipulation and expression of the VGSC a-subunit genes has proved to be a considerable challenge for a combination of reasons. The very large cDNAs tend to be highly unstable with a high rate of spontaneous rearrangement, deletion and point mutation. This is

Conclusion

Although empirical pharmacology has yielded many drugs acting at VGSCs, a more rational approach is required to exploit the full therapeutic potential in this area. Current drugs have low potency and it is now possible to screen recombinant VGSCs in order to identify more potent inhibitors with reduced compound-based adverse reactions. Current drugs are also rela-tively non-specific, targeting VGSCs and other ion channels. It is now feasible to screen for subtype selective drugs that might have

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