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(2006) lies in the regulatory effect of spermine on capsaicin-evoked TRPV1 currents. Results from our study showed that high (3 mm) but not lower Osimertinib price concentrations (10 ? 1000 ��m) of spermine significantly inhibited the capsaicin-evoked current (Fig. 2). The findings of Ahern et al. (2006) were a little complicated, in that low concentrations of spermine (1 ? 100 ��m) increased capsaicin-evoked currents in mouse nodose neurons, whereas in TRPV1-expressing oocytes spermine (1 mm) enhanced the response to a subsaturated concentration of capsaicin, reduced the response to a saturated concentration of capsaicin and had no effect on the response to an intermediate concentration of capsaicin. The reason for the disagreement between these two studies is not known. However, we assume that the aforementioned discrepancy could largely result from the differences in ECS and ICS used in these studies; we used 1.8 and 1.0 mm Ca2+ in the ECS and ICS, respectively, whereas no Ca2+ was included in either the ECS or the ICS in the study by Ahern et al. (2006). Firstly, CaSR might not be active in their study when Ca2+ was absent in either recording solution. Secondly, as TRPV1 has a high membrane permeability to Ca2+, selleck kinase inhibitor as described earlier, the capsaicin-evoked current in our experiments was supposedly carried mainly by Ca2+, whereas any inward currents studied by Ahern et al. (2006)were likely to be mediated only by Na+. In addition, the differences in other experimental conditions, such as cells and species used, as well as the method of chemical application, may also have contributed to the discrepancy between these two studies. Nevertheless, our results showed that the effect of spermine on capsaicin-evoked currents was closely mimicked by NPS R-568, a selective agonist of CaSR (Fig. 3), and the GPX4 effect of NPS R-568 was completely prevented by a specific CaSR antagonist, NPS 2143 (Fig. 6). Together, these data suggest that the inhibitory effect of spermine on the capsaicin response was indeed mediated through the activation of CaSR. Although the physiological relevance of our findings in the present study is not yet clear, we speculate that CaSR may play a role in controlling the excitability of vagal bronchopulmonary sensory neurons via cell-specific regulation of certain ion channels, such as TRPV1 and BKCa. For example, during high neuronal activity, the local decrease in extracellular Ca2+ results in an increased neuronal excitability. On the contrary, the increase in extracellular Ca2+ in circumstances such as local inflammation leads to a decreased neuronal excitability. In addition, CaSR is known to recognize a wide range of substances, including endogenous polyamines (e.g. spermine and spermidine) that are present at high concentrations inside neurons and can be released into the extracellular space (Quinn et al. 1997; Masuko et al. 2003); up to ?2.8 mm spermine has been reported in synaptic vesicles from rat brain tissues (Masuko et al. 2003).