Interactions Between Kisspeptins and Neurokinin B - Kisspeptin Signaling in Reproductive Biology - page 320

All three tachykinin receptors are encoded by genes divided into fi ve exons with
identical distribution of intronic sequences. NK3R, encoded by TACR3 in humans
and Tacr3 in rodents, leads to a longer amino acid sequence than NK1R or NK2R,
with a slight difference in length between species (465 and 452 residues in humans
and rats, respectively) [ 16 ].
NK3R is mainly located in the central nervous system (CNS) and the spinal cord
[ 15 , 16 , 36 ], although it has been also described in uterus, mesenteric vein, gut neu-
rons, and placenta [ 37 , 38 ]. Within the CNS of the rat, Tacr3 mRNA is detected in
the olfactory bulb, cortex, amygdala, hippocampus, medial habenula, zona incerta,
substantia nigra, ventral tegmental area, interpeduncular nucleus, raphe nuclei, dor-
sal tegmental nucleus, nucleus of the solitary tract, striatum, dentate gyrus and
subiculum, medial septum, diagonal band of Broca, ventral pallidum, globus palli-
dus, bed nucleus of the stria terminalis, ARC, paraventricular and supraoptic nuclei
of the hypothalamus, dorsal and lateral regions of the posterior hypothalamus, pre-
mammillary and mammillary nuclei, midbrain central gray, cerebellum, parabra-
chial nuclei, nucleus of the spinal trigeminal tract, dorsal horn of the spinal cord,
and the retina (Fig. 15.2 ) [ 22 , 29 , 39 - 41 ]. Of note, Tacr3 shows a maturational
process in the distribution of the expression of the gene along postnatal develop-
ment. Thus, prepubertal animals show more abundant expression in the amygdala
(basolateral amygdalar nucleus and basomedial amygdalar nucleus) and LHA than
peripubertal animals [ 40 ]. At the protein level, immunohistochemistry studies
depicting the distribution of NK3R resemble the brain areas where the Tacr3 mes-
senger is detected [ 25 , 29 , 42 - 45 ].

Regulation of the NKB/NK3R System by Sex Steroids

It is well established that gonadal steroids, i.e., estrogens and testosterone, feed
back to the CNS to exert a key role in the central control of the reproductive axis
by regulating the tonic release of GnRH (negative feedback) and the preovulatory
surge-like release of GnRH in females (positive feedback) [ 46 ]. In spite of this,
neurons that synthesize GnRH cannot respond directly to the homeostatic feed-
back of sex steroids, i.e., GnRH cells express neither estrogen receptor alpha
(ER α ) nor androgen receptor (AR) [ 47 , 48 ] and only a subset express ER β [ 49 ,

50 ]. However, the action of ER in GnRH neurons, while not yet well character-

ized, does not seem to be critical for, at least, the negative feedback control of sex
steroids upon GnRH release although, of note, it may participate in the regulation
of the excitability of GnRH neurons [ 51 ]. In this context, it is tenable that the
actions of sex steroid hormones on the reproductive axis must target upstream
modulators of GnRH neurons, such us (probably) NKB neurons in the ARC.
Thus, in keeping with this proposed role, this population of NKB neurons may
directly sense circulating levels of estradiol (E 2 ) and testosterone (T) through the
expression of ER

β

[ 22 , 52 - 56 ] and AR [ 57 , 58 ]. A number of studies in adult
mammals have demonstrated that, indeed, these ARC neurons exhibit a robust

α