The role of transient receptor potential ankyrin 1 (TRPA1) receptor activation in hydrogen-sulphide-induced CGRP-release and vasodilation.

Activation of transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) channels on capsaicin-sensitive sensory neurons causes release of inflammatory neuropeptides, including calcitonin gene-related peptide (CGRP). We investigated whether the hydrogen sulphide (H(2)S)-evoked CGRP release from sensory neurons of isolated rat tracheae and H(2)S-induced increases in the microcirculation of the mouse ear were mediated by TRPA1 receptor activation. Allylisothiocyanate (AITC) or the H(2)S donor sodium hydrogen sulphide (NaHS) were used as stimuli and CGRP release of the rat tracheae was measured by radioimmunoassay. AITC or NaHS were applied to the ears of Balb/c, C57BL/6, TRPA1 and TRPV1 receptor gene knockout mice and blood flow was detected by laser Doppler imaging. Both AITC and NaHS increased CGRP release from isolated rat tracheae, and both responses were inhibited by the TRPA1 antagonist, HC-030031, but was not affected by the TRPV1 receptor blocker, BCTC. Application of AITC or NaHS increased the cutaneous blood flow in the mouse ears. Similarly to the effect of AITC, the vasodilatory response to NaHS was reduced by HC-030031 or in TRPA1 deleted mice. In contrast, genetic deletion of TRPV1 did not affect the increase in the ear blood flow evoked by AITC or NaHS. We conclude that H(2)S activates TRPA1 receptors causing CGRP release from sensory nerves of rat tracheae, as well as inducing cutaneous vasodilatation in the mouse ear. TRPV1 receptors were not involved in these processes. Our results highlight that TRPA1 receptor activation should be considered as a potential mechanism of vasoactive effects of H(2)S.

Pozsgai G ，Hajna Z ，Bagoly T ，Boros M ，Kemény Á ，Materazzi S ，Nassini R ，Helyes Z ，Szolcsányi J ，Pintér E ... -  《-》

Capsaicin-Sensitive Sensory Nerves Mediate the Cellular and Microvascular Effects of H2S via TRPA1 Receptor Activation and Neuropeptide Release.

Hajna Z ，Sághy É ，Payrits M ，Aubdool AA ，Szőke É ，Pozsgai G ，Bátai IZ ，Nagy L ，Filotás D ，Helyes Z ，Brain SD ，Pintér E ... -  《-》

A novel 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime compound is a potent Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1 and V1) receptor antagonist.

Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1, TRPV1) ion channels expressed on nociceptive primary sensory neurons are important regulators of pain and inflammation. TRPA1 is activated by several inflammatory mediators including formaldehyde and methylglyoxal that are products of the semicarbazide-sensitive amine-oxidase enzyme (SSAO). SZV-1287 is a new 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime SSAO inhibitor, its chemical structure is similar to other oxime derivatives described as TRPA1 antagonists. Therefore, we investigated its effects on TRPA1 and TRPV1 receptor activation on the cell bodies and peripheral terminals of primary sensory neurons and TRPA1 or TRPV1 receptor-expressing cell lines. Calcium influx in response to the TRPA1 agonist allyl-isothiocyanate (AITC) (200 μM) and the TRPV1 stimulator capsaicin (330 nM) in rat trigeminal neurons or TRPA1 and TRPV1 receptor-expressing cell lines was measured by microfluorimetry or radioactive (45)Ca(2+) uptake experiments. Calcitonin gene-related peptide (CGRP) release as the indicator of 100 μM AITC - or 100 nM capsaicin-induced peripheral sensory nerve terminal activation was measured by radioimmunoassay. SZV-1287 (100, 500 and 1000 nM) exerted a concentration-dependent significant inhibition on both AITC- and capsaicin-evoked calcium influx in trigeminal neurons and TRPA1 or TRPV1 receptor-expressing cell lines. It also significantly inhibited the TRPA1, but not the TRPV1 activation-induced CGRP release from the peripheral sensory nerve endings in a concentration-dependent manner. In contrast, the reference SSAO inhibitor LJP 1207 with a different structure had no effect on TRPA1 or TRPV1 activation in either model system. This is the first evidence that our novel oxime compound SZV-1287 originally developed as a SSAO inhibitor has a potent dual antagonistic action on TRPA1 and TRPV1 ion channels on primary sensory neurons.

Payrits M ，Sághy É ，Mátyus P ，Czompa A ，Ludmerczki R ，Deme R ，Sándor Z ，Helyes Z ，Szőke É ... -  《-》

H(2)S functions as a nociceptive messenger through transient receptor potential ankyrin 1 (TRPA1) activation.

Hydrogen sulfide (H(2)S), an endogenous gasotransmitter, modulates various biological functions, including nociception. It is known that H(2)S causes neurogenic inflammation and elicits hyperalgesia. Here we show that H(2)S activates mouse transient receptor potential ankyrin 1 (TRPA1) channels and elicits acute pain, using TRPA1-gene deficient mice (TRPA1(-/-)) and heterologous expression system. In wild-type mouse sensory neurons, H(2)S increased the intracellular Ca(2+) concentration ([Ca(2+)](i)), which was inhibited by ruthenium red (a nonselective TRP channel blocker) and HC-030031 (a TRPA1 blocker). H(2)S-responsive neurons highly corresponded to TRPA1 agonist-sensitive ones. [Ca(2+)](i) responses to H(2)S were observed in neurons from transient receptor potential vanilloid 1 (TRPV1(-/-)) mice but not from TRPA1(-/-) mice. Heterologously expressed mouse TRPA1, but not mouse TRPV1, was activated by H(2)S. H(2)S-induced [Ca(2+)](i) responses were inhibited by dithiothreitol, a reducing agent. Analyses of the TRPA1 mutant channel revealed that two cysteine residues located in the N-terminal internal domain were responsible for the activation by H(2)S. Intraplantar injection of H(2)S into the mouse hind paw caused acute pain which was significantly less in TRPA1(-/-) mice. The [Ca(2+)](i) responses to H(2)S in sensory neurons and in heterologously expressed channels, and pain-related behavior induced by H(2)S were enhanced under acidic conditions. These results suggest that H(2)S functions as a nociceptive messenger through the activation of TRPA1 channels. TRPA1 may be a therapeutic target for H(2)S-related algesic action, especially under inflammatory conditions.

Ogawa H ，Takahashi K ，Miura S ，Imagawa T ，Saito S ，Tominaga M ，Ohta T ... -  《-》

Loss of capsaicin-induced meningeal neurogenic sensory vasodilatation in diabetic rats.

Dux M ，Rosta J ，Pintér S ，Sántha P ，Jancsó G ... -  《NEUROSCIENCE》