Acid-induced modulation of airway basal tone and contractility: Role of acid-sensing ion channels (ASICs) and TRPV1 receptor

Extracellular acidification stimulates IL-6 production and Ca2+mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells

“…MAP kinases and transcriptional factor NF-B have been shown to be involved in IL-6 production in ASMCs (5,17,20). We first examined whether an acidic pH or TNF␣ induces phosphorylation of MAP kinases and NF-B (Fig.…”

“…The pH of the airway of healthy subjects is in the range of 7.5 to 7.7, and that of patients with asthma is from 5.2 to 7.1, depending on the severity (26,40). It is known that protons sensitize the capsaicin-sensitive TRPV1 channel and/or ASICs in sensory nerves, producing local axonal reflexes with the subsequent release of tachykinins for the induction of cough and other asthmatic symptoms (17,40). However, it has also been shown that a variety of cell types implicated in airway dysfunction and inflammation can sense extracellular protons, resulting in changes in diverse cellular functions under conditions without nerve influences (28,40), suggesting the presence of mechanisms other than proton-sensing ion channels.…”

“…Moreover, asthma symptoms are known to be exacerbated by acid stress to the airway caused by gastro-esophageal reflux disease (40). Previous studies have shown that the proton-sensing capsaicin-sensitive TRPV1 channel and/or acid-sensing ion channels (ASICs) in sensory nerves play critical roles in the initiation and development of asthmatic symptoms (17,29,40). However, a variety of cell types implicated in airway dysfunction and inflammation can sense extracellular protons without nerve influences, resulting in changes in the diverse cellular functions (28,40).…”

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…For example, proton activation of vanilloid receptor subtype 1 (transient receptor potential vanilloid 1, TRPV1) on sensory neurons can induce membrane depolarization and stimulate local release of kinins (98,253). In addition to expression in airway neurons (70,176), there is limited evi- ]i levels but intriguingly results in bronchodilation via mechanisms that remain to be established. Ca 2ϩ -activated K ϩ channels (BKCa) and inhibition of voltage-gated Ca 2ϩ channels are thought to be involved, but pathways such as inhibition of other Ca 2ϩ influx mechanisms, mitochondria, or contractile mechanisms downstream to Ca 2ϩ may also be relevant.…”

“…Thus it would be interesting to determine whether OGR1 can indirectly influence these mechanisms. There has been considerable interest in acid-sensing ion channels (ASICs) on sensory neurons (98,99,172), but the limited evidence in ASM suggests that ASICs may actually contribute to pH-induced ASM relaxation (70). In PC12 cells, changes in extracellular pH can influence store-operated Ca 2ϩ influx that is dependent on the SR Ca 2ϩ protein stromal interacting molecule 1 (STIM1) (299).…”