Regulation of cough and action potentials by voltage-gated Na channels

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Abstract

The classical role ascribed to voltage-gated Na channels is the conduction of action potentials. Some excitable tissues such as cardiac muscle and skeletal muscle predominantly express a single voltage-gated Na channels isoform. Of the nine voltage-gated Na channels, seven are expressed in neurons, of these Nav 1.7, 1.8 and 1.9 are expressed in sensory neurons including vagal sensory neurons that innervate the airways and initiate cough. Nav 1.7 and Nav 1.9 are of particular interest as they represent two extremes in the functional diversity of voltage-gated Na channels. Voltage-gated Na channel isoforms expressed in airway sensory neurons produce multiple distinct Na currents that underlie distinct aspects of sensory neuron function. The interaction between voltage-gated Na currents underlies the characteristic ability of airway sensory nerves to encode encounters with irritant stimuli into action potential discharge and evoke the cough reflex.

Introduction

An urge to cough is initiated when sensory nerve endings within the airways encounter tussive stimuli. Tussive stimuli may activate any of the variety of transducers expressed within the nerve ending to generate a non-propagated depolarization known as a generator potential. A generator potential of sufficient magnitude to activate voltage-gated Na channels will in turn evoke a series of propagated depolarizations known as action potentials. Action potential discharge frequency is determined by the magnitude of the stimuli, the greater the magnitude of the stimuli the greater the frequency. Action potentials are conducted along nerve axons toward the central nervous system, the arrival of action potentials depolarizes the central terminal activating voltage-gated Ca channels allowing the entry of Ca that in turn triggers the release of neurotransmitter, thereby triggering central neural circuits to generate a cough reflex.

Of the nine voltage-gated Na channels isoforms, seven are expressed in neurons, of these Nav 1.7, 1.8 and 1.9 are expressed predominately in sensory neurons including vagal sensory neurons that innervate the airways and initiate cough [1]. The nine isoforms have been cloned, expressed and it is apparent that there are clear differences in the properties between isoforms. Nav 1.7 and Nav 1.9 are known to be expressed in airway sensory neurons [1] and are of particular interest as they represent two extremes in the functional diversity of voltage-gated Na channels.

Section snippets

Nav 1.9

Unlike typical voltage-gated Na currents that require large, rapid depolarizations to be activated, Nav 1.9 carries a persistent current that is activated at potentials close to resting potentials [2]. We sought to investigate the role of Nav 1.9 in vagal afferent neurons using whole-cell patch clamp recordings from dissociated neurons and single fiber recordings from vagal sensory neurons innervating ex-vivo lungs from Nav 1.9−/− mice and their wild-type (+/+) littermates [3]. While these mice

Nav 1.7

At the mRNA level, Nav 1.7 is one of the most abundantly expressed voltage-gated Na channel in vagal ganglia [1]. To evaluate the role specifically of Nav 1.7 in vagal afferent neurons we developed a technique using adeno-associated viruses to directly introduce shRNA to selectively inhibit Nav 1.7 expression in the vagal sensory ganglia of guinea pigs in vivo [4]. Nav 1.7 gene expression in nodose ganglia was effectively and selectively reduced without influencing the expression of other

Conclusions

Local anesthetics block all voltage-gated Na channel isoforms and are used to suppress cough during airway intubation [5], [6] and have been used to treat disease associated cough [7], [8], [9]. An understanding that sensory neurons express multiple voltage-gated Na channels has stimulated efforts to make next-generation Na channel blockers that combine the efficacy of local anesthetics with an increased therapeutic index.

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