scholarly journals Regulation of acid signaling in rat pulmonary sensory neurons by protease-activated receptor-2

2010 ◽  
Vol 298 (3) ◽  
pp. L454-L461 ◽  
Author(s):  
Qihai Gu ◽  
Lu-Yuan Lee
Keyword(s):  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Inflammatory Conditions ◽  
C Fibers ◽  
Inward Currents ◽  
Transient Receptor ◽  
Protease Activated Receptor 2 ◽  
Airway Acidification

Airway acidification has been consistently observed in airway inflammatory conditions and is known to cause cardiorespiratory symptoms that are, at least in part, mediated through the activation of bronchopulmonary C fibers and the subsequent reflexes. Protease-activated receptor-2 (PAR2) is expressed in a variety of cells in the lung and airways and is believed to play a role in airway inflammation and hyperresponsiveness. This study was carried out to investigate the effect of PAR2 activation on the acid signaling in rat bronchopulmonary C-fiber sensory neurons. Our RT-PCR results revealed the expression of mRNAs for transient receptor potential vanilloid receptor 1 (TRPV1) and four functional acid-sensing ion channel (ASIC) subunits 1a, 1b, 2a, and 3 in these sensory neurons. Preincubation of SLIGRL-NH2, a specific PAR2-activating peptide, markedly enhanced the Ca2+ transient evoked by extracellular acidification. Pretreatment with PAR2 agonists significantly potentiated both acid-evoked ASIC- and TRPV1-like whole cell inward currents. Activation of PAR2 also potentiated the excitability of these neurons to acid, but not electrical stimulation. In addition, the potentiation of acid-evoked responses was not prevented by inhibiting either PLC or PKC nor was mimicked by activation of PKC. In conclusion, activation of PAR2 modulates the acid signaling in pulmonary sensory neurons, and the interaction may play a role in the pathogenesis of airway inflammatory conditions, where airway acidification and PAR2 activation can occur simultaneously.

Protease-activated receptor-2 activation exaggerates TRPV1-mediated cough in guinea pigs

2006 ◽  
Vol 101 (2) ◽  
pp. 506-511 ◽  
Author(s):  
Raffaele Gatti ◽  
Eunice Andre ◽  
Silvia Amadesi ◽  
Thai Q. Dinh ◽  
Axel Fischer ◽  
...  
Keyword(s):  
Citric Acid ◽  
Sensory Neurons ◽  
Guinea Pigs ◽  
Transient Receptor Potential ◽  
Inflammatory Diseases ◽  
Receptor Potential ◽  
Chronic Obstructive ◽  
Transient Receptor Potential Vanilloid ◽  
Independent Manner ◽  
Protease Activated Receptor 2

A lowered threshold to the cough response frequently accompanies chronic airway inflammatory conditions. However, the mechanism(s) that from chronic inflammation results in a lowered cough threshold is poorly understood. Irritant agents, including capsaicin, resiniferatoxin, and citric acid, elicit cough in humans and in experimental animals through the activation of the transient receptor potential vanilloid 1 (TRPV1). Protease-activated receptor-2 (PAR2) activation plays a role in inflammation and sensitizes TRPV1 in cultured sensory neurons by a PKC-dependent pathway. Here, we have investigated whether PAR2 activation exaggerates TRPV1-dependent cough in guinea pigs and whether protein kinases are involved in the PAR2-induced cough modulation. Aerosolized PAR2 agonists (PAR2-activating peptide and trypsin) did not produce any cough per se. However, they potentiated citric acid- and resiniferatoxin-induced cough, an effect that was completely prevented by the TRPV1 receptor antagonist capsazepine. In contrast, cough induced by hypertonic saline, a stimulus that provokes cough in a TRPV1-independent manner, was not modified by aerosolized PAR2 agonists. The PKC inhibitor GF-109203X, the PKA inhibitor H-89, and the cyclooxygenase inhibitor indomethacin did not affect cough induced by TRPV1 agonists, but abated the exaggeration of this response produced by PAR2 agonists. In conclusion, PAR2 stimulation exaggerates TRPV1-dependent cough by activation of diverse mechanism(s), including PKC, PKA, and prostanoid release. PAR2 activation, by sensitizing TRPV1 in primary sensory neurons, may play a role in the exaggerated cough observed in certain airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia

2008 ◽  
Vol 294 (5) ◽  
pp. G1288-G1298 ◽  
Author(s):  
Walter E. B. Sipe ◽  
Stuart M. Brierley ◽  
Christopher M. Martin ◽  
Benjamin D. Phillis ◽  
Francisco Bautista Cruz ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Action Potentials ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mechanical Hyperalgesia ◽  
Transient Receptor Potential Vanilloid ◽  
Afferent Neurons ◽  
Nociceptive Neurons ◽  
Afferent Fibers ◽  
Transient Receptor

Protease-activated receptor (PAR2) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR2 cause hyperexcitability of intestinal sensory neurons and hyperalgesia to distensive stimuli by unknown mechanisms. We evaluated the role of the transient receptor potential vanilloid 4 (TRPV4) in PAR2-induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR2, and calcitonin gene-related peptide and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distension (CRD) were measured by electromyography of abdominal muscles. In TRPV4+/+ mice, intraluminal PAR2 activating peptide (PAR2-AP) exacerbated VMR to graded CRD from 6–24 h, indicative of mechanical hyperalgesia. PAR2-induced hyperalgesia was not observed in TRPV4−/− mice. PAR2-AP evoked discharge of action potentials from colonic afferent neurons in TRPV4+/+ mice, but not from TRPV4−/− mice. The TRPV4 agonists 5′,6′-epoxyeicosatrienoic acid and 4α-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely labeled colonic dorsal root ganglia neurons, confirming expression of functional TRPV4. PAR2-AP enhanced these responses, indicating sensitization of TRPV4. Thus TRPV4 is expressed by primary spinal afferent neurons innervating the colon. Activation of PAR2 increases currents in these neurons, evokes discharge of action potentials from colonic afferent fibers, and induces mechanical hyperalgesia. These responses require the presence of functional TRPV4. Therefore, TRPV4 is required for PAR2-induced mechanical hyperalgesia and excitation of colonic afferent neurons.

Thermal sensitivity of isolated vagal pulmonary sensory neurons: role of transient receptor potential vanilloid receptors

2006 ◽  
Vol 291 (3) ◽  
pp. R541-R550 ◽  
Author(s):  
Dan Ni ◽  
Qihai Gu ◽  
Hong-Zhen Hu ◽  
Na Gao ◽  
Michael X. Zhu ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Thermal Sensitivity ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Transient Receptor Potential Vanilloid ◽  
Temperature Sensitive ◽  
Inward Current ◽  
Transient Receptor ◽  
Increasing Temperature

A recent study has demonstrated that increasing the intrathoracic temperature from 36°C to 41°C induced a distinct stimulatory and sensitizing effect on vagal pulmonary C-fiber afferents in anesthetized rats ( J Physiol 565: 295–308, 2005). We postulated that these responses are mediated through a direct activation of the temperature-sensitive transient receptor potential vanilloid (TRPV) receptors by hyperthermia. To test this hypothesis, we studied the effect of increasing temperature on pulmonary sensory neurons that were isolated from adult rat nodose/jugular ganglion and identified by retrograde labeling, using the whole cell perforated patch-clamping technique. Our results showed that increasing temperature from 23°C (or 35°C) to 41°C in a ramp pattern evoked an inward current, which began to emerge after exceeding a threshold of ∼34.4°C and then increased sharply in amplitude as the temperature was further increased, reaching a peak current of 173 ± 27 pA ( n = 75) at 41°C. The temperature coefficient, Q10, was 29.5 ± 6.4 over the range of 35–41°C. The peak inward current was only partially blocked by pretreatment with capsazepine (Δ I = 48.1 ± 4.7%, n = 11) or AMG 9810 (Δ I = 59.2 ± 7.8%, n = 8), selective antagonists of the TRPV1 channel, but almost completely abolished (Δ I = 96.3 ± 2.3%) by ruthenium red, an effective blocker of TRPV1–4 channels. Furthermore, positive expressions of TRPV1–4 transcripts and proteins in these neurons were demonstrated by RT-PCR and immunohistochemistry experiments, respectively. On the basis of these results, we conclude that increasing temperature within the normal physiological range can exert a direct stimulatory effect on pulmonary sensory neurons, and this effect is mediated through the activation of TRPV1, as well as other subtypes of TRPV channels.

Sign in / Sign up

Export Citation Format

Share Document