Abstract
We previously demonstrated that the canine nociceptor response to bradykinin (BK) was sensitized by agonist of prostaglandin receptor EP3 and decreased by cAMP-increasing reagents. In Chinese hamster ovary cells expressing EP3 cloned from canine dorsal root ganglia and mouse BK B2 receptor, we examined the effects of EP3 agonist, ONO-AE-248, and a specific inhibitor of protein kinase A (PKA), H-89, on the [Ca2+]i increase induced by BK. When BK (1 nM) was applied twice with a 6-min interval, the second response (maximal [Ca2+]i increase) was markedly attenuated to approximately 50% of the initial one. ONO-AE-248 (0.1 μM) significantly restored this attenuation to more than 80% in a PTX-sensitive manner without inducing any change in [Ca2+]i by itself. The pretreatment with H-89 (1 μM) also restored the second response. Both reagents had no effect on the initial BK response. These results demonstrate that BK-induced desensitization of BK B2 receptor is a slower event than the BK-induced [Ca2+]i increase and that the activation of EP3 restores the response to BK by attenuating the BK-induced desensitization of BK B2 receptor through activation of Gi protein and thus downregulation of PKA. [J Physiol Sci. 2007;57 Suppl:S112]
