Voltage-gated sodium channels

doi:10.1016/j.coph.2015.04.007

Current Opinion in Pharmacology

Volume 22, June 2015, Pages 131-139

https://doi.org/10.1016/j.coph.2015.04.007 Get rights and content

Highlights

•
Voltage-gated sodium channels (Na_V) play a key role in neuronal excitability.
•
Individual nerves express multiple Na_V subtypes.
•
Many Na_V mutations are associated with gain or loss of function.
•
Efforts are underway to develop Na_V subtype-specific Na_V blockers.

Voltage-gated sodium channels play a key role in the transmission of sensory information about the status of organs in the periphery. Sensory fibers contain a heterogeneous yet specific distribution of voltage-gated sodium channel isoforms. Major efforts by industry and academic groups are underway to develop medicines that interrupt inappropriate signaling for a number of clinical indications by taking advantage of this specific distribution of channel isoforms. This review highlights recent advances in the study of human channelopathies, animal toxins and channel structure that may facilitate the development of selective voltage-gated sodium channel blockers.

Introduction

The expression of voltage-gated sodium channels (Na_Vs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. This includes the neurons that innervate the airway whose activity underlies important respiratory sensations such as dyspnea and reflexes including cough and bronchoconstriction. Neurons, in particular sensory neurons, typically express multiple Na_V isoforms (Table 1). This raises the question of how each isoform contributes to action potential initiation and conduction. In this review we focus on recent findings that have started to address this important question as well as efforts to develop the next generation of Na_V blockers as therapeutics.

Section snippets

Gain-of-function and loss-of-function mutations

Over the last decade great strides have been made toward elucidating the molecular and genetic underpinnings of pain. A number of painful and painless neuropathies have been linked to mutations on SCN9A, which encodes Na_V1.7 α-subunit [1, 2, 3, 4, 5]. Excellent reviews can be found in [6, 7••]. Additional neuropathies have been identified that segregate with mutations on SCN10A and SCN11A, which encode the α-subunits of Na_V1.8 and Na_V1.9, respectively [8, 9, 10, 11, 12, 13]. Na_V1.7, Na_V1.8 and

Small molecule blockers in clinical trials

Currently marketed Na_V blockers such as lidocaine, amitriptyline and lamotrigine have been used with some success for the relief of pain and cough [4, 25, 26]. However, their use is limited due to safety issues owning to their inability to discriminate among channel isoforms. A number of companies are developing the second generation of small molecules that are isoform-selective Na_V blockers. Listed in Table 2 are the most advanced clinical assets being tested in patients. Excellent reviews of

Animal toxins

Animals have evolved to utilize ingenious strategies for predation and defense. Sea anemones, cone snails, spiders, scorpions, octopi, and puffer fish, to name a few, employ chemical or peptide toxins to overcome prey that sometimes have far greater mobility than the predator. Voltage-gated sodium channels are essential for locomotion — Na_V1.4 in skeletal muscle, neuronal Na_V isoforms (e.g. Na_V1.1–1.3 and Na_V1.6–1.9) to drive or coordinate muscle activity and Na_V1.5 in the heart to supply blood

Selective monoclonal antibody targeting Na_V1.7

The current generation of marketed drugs to block Na_V channels for pain and respiratory indications are non-selective and therefore risk blocking cardiac and muscle isoforms. To improve therapeutic index a number of strategies have been developed to improve the safety profile of the drugs, including topical delivery and reliance on frequency-dependent blockade. Alternatively a number of groups have leveraged the exquisite specificity of antibodies to achieve isoform selectivity in K_V, Ca_V as

Conclusions

The recognition that particular isoforms may play unique non-redundant roles has lead to the search for novel blockers that target particular Na_V isoforms in the hope that such selective pharmacological agents will be useful in treating diseases associated with aberrant reflexes and neuronal activity. Given that the nervous system innervating the lungs and airways contributes to cough and reflex bronchoconstriction-associated respiratory diseases and given our emerging understanding of the

Conflict of interest statement

Michael J Carr & Kevin Kwong are full time employees of GSK.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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