The Integrated Tachykinin-Kisspeptin System as a Novel Coordinator of the Control of Gonadotropin Release in the Mouse

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 112-141-Hypothalamus-Pituitary Development & Biology
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-129
Victor Manuel Navarro*1, Min Wu2, Rona S. Carroll1, Meenakshi Alreja3 and Ursula B Kaiser4
1Brigham and Women's Hospital, Boston, MA, 2Yale University, 3Yale University School of Medici, New Haven, CT, 4Brigham Women's/Harvard Med Sc, Boston, MA
Tachykinins are a family of closely related neuropeptides comprising substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), which predominantly bind neurokinin-1 receptor (NK1R), NK2R and NK3R, respectively. NKB co-localizes with kisspeptin and dynorphin in neurons of the hypothalamic arcuate nucleus in rodents, so-called KNDy neurons. Kisspeptin is the most potent GnRH secretagogue identified to date and NKB has been suggested to play a role—along with dynorphin—in the shaping of kisspeptin/GnRH pulses through auto-synaptic loops on KNDy neurons. Indeed, studies in rodents, sheep and monkeys document a kisspeptin-dependent stimulatory action of NKB on gonadotropin release, depending on the sex steroid milieu. However, the reproductive roles, if any, of SP and NKA remain unknown. In this work, we aimed to characterize and compare the actions of SP, NKA and NKB on gonadotropin release by using specific agonists for their corresponding receptors: GR73632 (NK1R), GR64349 (NK2R) and senktide (NK3R) through a series of functional studies in adult male mice. Central (intracerebroventricular) administration of these specific agonists (600 pmol each) resulted in significant increases of serum LH and FSH levels 25 min after treatment in all three cases. These effects were equivalent to or even greater than that evoked by NKB, used as a positive control. Additionally, we assessed the effects of these agonists on arcuate Kiss1 neurons from adult male Kiss1-GFP mice through electrophysiological whole-cell recordings. We observed neuronal activation following a 15-30 s challenge with 1-10 μM of each agonist. Importantly, GnRH-GFP neurons remained unresponsive to the same challenges, suggesting a specific effect on Kiss1 neurons. In sum, we document the stimulatory action on gonadotropin release following the specific stimulation of all three tachykinin receptors and hence provide support for a regulatory role of SP and NKA in the central control of GnRH release through, at least in part, the stimulation of KNDy neurons—similar to that described for NKB.

Nothing to Disclose: VMN, MW, RSC, MA, UBK

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Sources of Research Support: NIH/NICHD K99HD071970