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Bradykinin Receptor Localization and Cell Signaling Pathways Used by Bradykinin in the Regulation of Gonadotropin-Releasing Hormone Secretion¹

Department of Physiology and Endocrinology, Medical College of Georgia, Augusta, Georgia 30912

Address all correspondence and requests for reprints to: Dr. Darrell W. Brann, Department of Physiology and Endocrinology, Medical College of Georgia, Augusta, Georgia 30912. E-mail: dbrann{at}mail.mcg.edu

In a previous publication we provided evidence of a novel neuronal pathway for the control of GnRH secretion by bradykinin. The action of bradykinin appeared to be exerted through the bradykinin B₂ receptor. In this study we demonstrated that the bradykinin B₂ receptor is densely localized in the arcuate nucleus, median eminence, organum vasculosum of the lamina terminalis, and preoptic area, regions known to be critical for the control of GnRH secretion. To determine the mechanism of action of bradykinin in stimulating GnRH release, we used immortalized GnRH (GT1–7) cells in vitro. Bradykinin stimulation of GnRH secretion from GT1–7 cells appears to involve activation of the phospholipase C signaling pathway and mobilization of extracellular and intracellular calcium stores. Evidence to support this contention was derived from the observations that incubation of the phospholipase C inhibitor, U-73122 with bradykinin, blocked the ability of bradykinin to stimulate release from GT1–7 cells. This effect was specific, as a nitric oxide synthase inhibitor and a cyclooxygenase inhibitor were found to have no effect on bradykinin-induced GnRH secretion, suggesting that nitric oxide and PGs do not mediate bradykinin effects. Pertussis toxin also had no effect on bradykinin action. This suggests that the bradykinin B₂ receptor may be coupled to a pertussis toxin-insensitive G protein in GT1–7 cells. With respect to calcium involvement in bradykinin action, fura-2 calcium indicator studies revealed that bradykinin can rapidly increase intracellular Ca²⁺ levels in GT1–7 cells. A role for intracellular Ca²⁺ in bradykinin action was further suggested by the finding that an intracellular calcium chelator, 1,2-bis(O-aminophenoxy)]ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester, significantly attenuated the effects of bradykinin on GnRH release. The elevation of intracellular calcium by bradykinin appears to be due to mobilization of calcium from the endoplasmic reticulum, as incubation of the Ca²⁺-adenosine triphosphatase inhibitor thapsigarin, which depletes endoplasmic reticulum Ca²⁺ stores, significantly attenuated bradykinin action on GnRH release. Extracellular calcium may also be involved in bradykinin action, as the L-type Ca²⁺ channel blockers verapamil and nifedipine had no effect on bradykinin-induced GnRH release, whereas the nonselective Ca²⁺ channel blocker, nickel chloride, attenuated bradykinin-induced GnRH release. Taken as a whole, these studies demonstrate that the bradykinin B₂ receptor is densely localized in key hypothalamic nuclei responsible for regulation of GnRH release, and that the mechanism of bradykinin stimulation of GnRH secretion involves activation of the phospholipase C signaling pathway, with a critical role implicated for calcium in bradykinin action in GT1–7 cells.

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