Characterization of the Role of NKA in the Control of Puberty Onset and Gonadotropin Release in the Female Mouse

Abstract

The tachykinin neurokinin B (NKB, Tac2) is critical for proper GnRH release in mammals, however, the role of the other tachykinins, such as substance P (SP) and neurokinin A (NKA) in reproduction, is still not well understood. In this study, we demonstrate that NKA controls the timing of puberty onset (similar to NKB and SP) and stimulates LH release in adulthood through NKB-independent (but kisspeptin-dependent) mechanisms in the presence of sex steroids. Furthermore, this is achieved, at least in part, through the autosynaptic activation of Tac1 neurons, which express NK2R (Tacr2), the receptor for NKA. Conversely, in the absence of sex steroids, as observed in ovariectomy, NKA inhibits LH through a mechanism that requires the presence of functional receptors for NKB and dynorphin (NK3R and KOR, respectively). Moreover, the ability of NKA to modulate LH secretion is absent in Kiss1KO mice, suggesting that its action occurs upstream of Kiss1 neurons. Overall, we demonstrate that NKA signaling is a critical component in the central control of reproduction, by contributing to the indirect regulation of kisspeptin release.

Novel Biology of Tachykinins in Gonadotropin-Releasing Hormone Secretion

“…Contrary to NKA and NKB, SP induces LH release regardless of the sex steroid milieu 26 ; however, there are also important species differences in this action. SP can potently stimulate LH release in mice, 26,27 prepubertal rats, 16,33 rabbits, 20 and humans, 18 but it has a very limited action in adult rats, 33 goats, 43 sheep, 54 and juvenile male monkeys, 55 similar to the effect described earlier for NKA.…”

“…26 In the absence of sex steroids (e.g., after gonadectomy), these tachykinins potently inhibit LH release in a process that is mediated by the stimulation of the inhibitory tone of the endogenous opioid peptide dynorphin A (Dyn). [26][27][28] This hormonal-dependent effect of NKA and NKB is present in both sexes and points to a role of these tachykinins in the regulation of the negative feedback of sex steroids upon GnRH release. Furthermore, this suggests that the primary action of NKA and NKB takes place on, or above, sex steroid-sensitive neurons (i.e., Kiss1 neurons) in a mechanism that may seem converging at the level of second messenger pathways within their target neurons.…”

“…In this regard, we have recently demonstrated that NKA is able to induce LH release in ovariectomized and estradiolreplaced mice in the absence of NKB (Tac2 knockout [KO] mice) and after blockade of the NKB receptor, NK3R (encoded by Tacr3). 27 These data rule out an NKB-dependent action of NKA as well as the cross-activation of NK3R by NKA-given the documented cross-reactivity for tachykinin receptors. 8,29 On the contrary, the inhibitory action of NKA on LH release is blunted after NK3R blockade, suggesting that the activation of the NKB-Dyn pathway is required for this action.…”

“…On one hand, mice depict a significant increase in LH in the presence of sex steroids at all tested ages, in a way that resembles that of NKB in their timing and magnitude. 26,27 Rats, on the other hand, only respond clearly to NKA prepuberally and this action is blunted or absent in adulthood. 33 This is in line with data in goats and sheep that demonstrate that the concentration of NKA needed to elicit LH secretion is several folds higher than that of NKB.…”

“…8,29 On the contrary, the inhibitory action of NKA on LH release is blunted after NK3R blockade, suggesting that the activation of the NKB-Dyn pathway is required for this action. 27 Interestingly, while NKB potently stimulates LH release under physiological sex steroid levels in rodents, 26,28,[30][31][32][33][34] sheep, [35][36][37][38][39][40] goats, [41][42][43] cattle, 44 and nonhuman primates, [45][46][47] its gonadotropin-stimulating role is not observed in adult healthy men 48 or women in the follicular phase. 49 Nonetheless, NK3R antagonists decrease overall circulating LH levels and LH pulsatility in humans, [50][51][52][53] suggesting that the role of NKB to elicit kisspeptin/GnRH pulses is conserved in all species, but the optimization of the delivery method and/or concentration of the NK3R agonists is required to observe a stimulation of LH release in humans.…”