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Investigating a role for acid sensing ion channels in the vagal sensory afferent response to low pH
A significant proportion of patients who suffer from inflammatory airways disease also present with chronic cough. An acidic environment is often present in the inflamed lung, and low pH solutions have been shown to activate airway sensory afferents and induce cough in animals and humans1. A decrease in lung pH may therefore play an important role in chronic cough, and thus in the search for effective medications, it is important to understand the mechanisms by which low pH activates airway sensory nerves. The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channels are thought to partially mediate the response to low pH in sensory afferent nerves that project to the airways in vitro; and in the cough reflex in vivo2-4. However, it is yet to be determined what other ion channel(s) are involved. Based on the activation profile of the non-TRPV1-dependent response to low pH in single fibres, and the expression profile of Acid Sensing Ion Channels (ASICs) in rat dorsal root ganglia, it has been suggested that ASICs may also be involved3. Our aim was therefore to determine whether ASICs mediate the non-TRPV1-dependent response to low pH in vagal sensory nerves. Low pH (pH5) caused robust depolarisation of guinea-pig, wild-type mouse and human sensory nerves, which were partially inhibited with a general ASIC channel antagonist (100 µM amiloride) or TRPV1-selective antagonist (100 µM JNJ-17203212). To investigate which subtype of ASIC was involved we used vagal tissue from genetically modified mice. Compared to wild-type (C57/Bl6), the magnitude of vagus nerve depolarisation with low pH stimulation was blunted in both Trpv1-/- and Asic1-/-, but not Asic3-/- mice. Furthermore, inhibition of ASIC ion channels in Trpv1-/-, and inhibition of TRPV1 in Asic1-/- mouse tissue virtually abolished low pH-induced nerve responses; whereas, inhibition of TRPV1 in Asic3-/- tissue did not inhibit low pH responses any more than in wild-type. In summary, TRPV1 and ASIC ion channels mediate vagal sensory afferent responses to low pH stimulation in rodent and human isolated tissue. Furthermore, using genetically modified mice, we have established that pH5 is acting on the ASIC1 channel subtype. This work provides a greater understanding of how low pH is activating sensory nerves at a pH which is known to activate TRPV1. More work and better pharmacological tools are needed to determine what ASIC subtype is mediating low pH responses in humans, and whether these ion channels are involved in the sensitisation of the cough reflex seen in inflammatory airway diseases.
1. Laude et al., 1993, Pulm. Pharmacol., 6: 171-175. |
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