Regulation of NKB Pathways and Their Roles in the Control of Kiss1 Neurons in the Arcuate Nucleus of the Male Mouse

Abstract

Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus (ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17β-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptor-dependent pathways; 3) senktide, an agonist for the NKB receptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male.

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“…In turn, NKB may act on KNDy neurons to finely tune (predominantly, stimulate) kisspeptin release, therefore inducing GnRH secretion in an indirect manner. This possibility is, at least partially, supported by a solid body of experimental evidence, including the following observations: i) central senktide injection induces expression of C-fos in ARC KNDy neurons (34); ii) senktide elicits LH secretion in a GnRH-dependent manner (28); iii) the LH-releasing effects of senktide are not detected in the absence of proper Gpr54 signaling (35); iv) desensitization to the effects of continuous NKB stimulation takes place at a level upstream of GnRH neurons (28); v) substantial NK3R expression is detected in KNDy, but not GnRH neurons, in rodents and sheep (23); and vi) senktide induces the electrical activation of Kiss1 neurons, as revealed by electrophysiological recordings in Kiss1-CreGFP mice (40). To add further refinement to the system, the third partner of the KNDy trio, Dyn, has been long recognized as an inhibitor of gonadotropin secretion, likely via its ability to repress the release of kisspeptins on of GnRH neurons (12).…”

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

“…KP neurons in the ARC have been shown to co-express NKB and dynorphin A (DYN) 131,[135][136][137] and have therefore been named KNDY neurons 135 . Since GnRH neurons express GPR54 but apparently not TACR3 132,137,138 , while KNDY do express TACR3, it was further postulated that NKB secreted from KNDY neurons acts in an autocrine or paracrine manner to enhance KP secretion and that NKB actions were upstream of KP 134 .…”

“…Since GnRH neurons express GPR54 but apparently not TACR3 132,137,138 , while KNDY do express TACR3, it was further postulated that NKB secreted from KNDY neurons acts in an autocrine or paracrine manner to enhance KP secretion and that NKB actions were upstream of KP 134 . This notion was supported by the demonstration that continuous infusion of KP at a GPR54-saturating concentration in patients with NKB and TACR3 inactivating mutations restored LH pulsatility 134 .…”

Differential modulation of gonadotropin responses to kisspeptin by aminoacidergic, peptidergic, and nitric oxide neurotransmission

“…As an illustrative example, neurokinin B (NKB), which is coexpressed in Kiss1 neurons in the arcuate (ARC) nucleus (25), has been shown to stimulate LH secretion in a Gpr54-dependent manner in rodents and primates (12,26,30,32,42,43), an observation that is in keeping with the reported state of hypogonadotropic hypogonadism in humans with inactivating mutations in the genes encoding NKB (TAC3), its receptor NK3R (TACR3), or GPR54 (33,34). Collectively, these and related findings have led to the hypothesis that NKB (auto)regulates Kp output from ARC Kiss1 neurons onto GnRH neurons (33,34,53).…”

“…Collectively, these and related findings have led to the hypothesis that NKB (auto)regulates Kp output from ARC Kiss1 neurons onto GnRH neurons (33,34,53). However, stimulatory, inhibitory, or null effects of the agonist of NKB, senktide, on LH secretion have been reported, depending on the sex steroid milieu and the functional state of the gonadotropic axis (5,22,30,32,42,43,48,51), a phenomenon whose basis remains unknown. Moreover, the ability of NKB to modulate GnRH/gonadotropin responses to Kp remains unexplored.…”