Intracellular Ca2+ mobilization pathway via bradykinin B1 receptor activation in rat trigeminal ganglion neurons

Bradykinin (BK) and its receptors, B-1 and B-2, in trigeminal ganglion (TG) neurons are involved in the regulation of pain. Recent studies have revealed that B-1 receptors are expressed in neonatal rat TG neurons; however, the intracellular signaling pathway following B-1 receptor activation remains to be elucidated. To investigate the mechanism by which B-1 receptor activation leads to intracellular Ca2+ mobilization, we measured the intracellular free Ca2+ concentration ([Ca2+](i)) in primary-cultured TG neurons. The application of Lys-[Des-Arg(9)]BK (B-1 receptor agonist) increased the [Ca2+](i) in these TG neurons even in the absence of extracellular Ca2+. Pretreatment with inhibitors of ryanodine receptors or sarco/endoplasmic reticulum Ca2+-ATPase suppressed the increase in Lys-[Des-Arg(9)]BK-induced [Ca2+](i). The Lys-[Des-Arg(9)]BK-induced [Ca2+](i) increase was unaffected by phospholipase-C inhibitor. B-1 receptor activation-induced [Ca2+](i) increase was suppressed by phosphodiesterase inhibitor and enhanced by adenylyl cyclase inhibitor. These results suggest that B-1 receptor activation suppresses intracellular cAMP production via adenylyl cyclase inhibition and mobilizes intracellular Ca2+ via ryanodine receptors that access intracellular Ca2+ stores.