TRPV1 as a cough sensor and its temperature-sensitive properties

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Abstract

In the respiratory tract, TRPV1, a non-selective cation channel and a polymodal transducer, is expressed primarily in non-myelinated sensory nerves. A significant role of TRPV1 in eliciting the cough reflex has been extensively documented. Inhalation of capsaicin aerosol, a selective agonist of TRPV1, consistently and reproducibly evoked coughs in a dose-dependent manner in both healthy humans and in patients with airway inflammatory diseases. A number of endogenous inflammatory mediators known to upregulate the TRPV1 sensitivity, such as prostaglandin E2 and bradykinin, also enhanced the cough sensitivity. Furthermore, a substantial increase of TRPV1-immunoreactive nerve profiles was found in the bronchial tissue of patients with chronic cough. In addition to the cough reflex, activation of TRPV1-expressing sensory nerves in the airways is also known to elicit reflex bronchoconstriction and mucus secretion mediated through cholinergic pathways. One of the physiological stimuli known to activate TRPV1 receptor directly is high temperature. Recent studies have demonstrated that increasing temperature within the normal physiological range significantly elevated the baseline activity and sensitivity of isolated rat vagal pulmonary sensory neurons, and the sensitizing effect of hyperthermia appeared to be mediated selectively through the TRPV1 channel. This temperature-sensitive property of TRPV1 may play an important role in regulating the physiological function of the TRPV1-expressing airway sensory nerves and the sensitivity of their reflex responses, such as cough and reflex bronchoconstriction.

Section snippets

Transient receptor potential vanilloid type 1 receptor (TRPV1) as a cough sensor

An involvement of TRPV1 receptor activation in eliciting the cough reflex has been extensively documented in several comprehensive reviews recently [35], [36], and therefore the background information about the TRPV1 as a cough sensor will only be briefly summarized in this mini-review. TRPV1, a polymodal transducer, is a tetrameric membrane protein with four identical subunits, each subunit containing six transmembrane-spanning domains, which form a non-selective cation channel [41]. The

Temperature-sensitive properties of TRPV1 expressed in airways sensory nerves

All four subtypes of TRPV channels, TRPV1–4, are recognized as the primary sensors for warm and hot temperatures in mammalian species, and each is activated at a different temperature threshold (>43 °C for TRPV1; >52 °C for TRPV2; >34–38 °C for TRPV3; >27–35 °C for TRPV4) [10]. Recent studies have demonstrated the expression of both mRNA and receptor proteins of all these four subtypes of TRPVs in the cell bodies of sensory neurons innervating the lung structures [38]. Although thermal

Conclusion

Collective evidence clearly indicates a significant role of TRPV1 expressed in airway sensory nerves in triggering the cough reflex in both healthy humans and in patients with airway inflammatory diseases [11], [13], [20], [27]. Recent studies have further revealed the stimulatory and sensitizing effects of increasing temperature on the responses of pulmonary sensory neurons to TRPV1 activators [38], [39], [40]. This sensitizing effect of hyperthermia appears to be mediated selectively through

Acknowledgements

This study was supported in part by NIH grant HL96914.

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