Kisspeptin Excitation of GnRH Neurons - Kisspeptin Signaling in Reproductive Biology - page 111

kisspeptin is not able to stimulate LH or FSH release in GPR54 knockout animals
[ 11 ]. Also, the kisspeptin-mediated release of LH is completely inhibited by the
GnRH antagonist, acyline [ 1 , 8 ]. Importantly, CNS administration of kisspeptin in
the ewe has conclusively demonstrated a correlation between kisspeptin-induced
GnRH and LH release [ 11 ]. Therefore, the stimulatory actions of kisspeptin appear
to be primarily on GnRH neurons and not the pituitary. Kisspeptin, when applied to
GnRH neurons in vitro, potently activates these neurons and causes increased neu-
ronal fi ring [ 12 - 14 ].
Over the past several years, there have been many publications about the regula-
tion of Kiss1 gene expression and the role of kisspeptins in regulating GnRH and
LH secretion [ 1 , 8 , 11 , 15 - 17 ]. Also, the distribution and regulation of kisspeptin
mRNA ( Kiss1 ) expression by 17 -estradiol (E 2 ) has been extensively described in

the mouse and rat brain [ 15 , 17 , 18 ]. In these rodent species, it is known that Kiss1
mRNA is expressed primarily in the anteroventral periventricular nucleus (AVPV)
and adjacent periventricular (PeN) areas, as well as in the arcuate nucleus of the
hypothalamus [ 19 , 20 ]. Importantly, E 2 increases the mRNA expression of Kiss1 in
the female AVPV, but decreases the expression in the arcuate nucleus [ 15 , 17 ].
These fi ndings are consistent with data showing that the AVPV is necessary for E 2
positive feedback on GnRH and LH secretion in these species [ 21 - 23 ]. The number
of AVPV kisspeptin neurons is signifi cantly fewer in male rodents than in females,
but the numbers are similar in the arcuate nucleus in adults of both sexes [ 24 ]. As in
females, steroid treatment (testosterone or E 2 ) increases the number of Kiss1 neu-
rons in the male AVPV and decreases the number of Kiss1 expressing cells in the
arcuate nucleus [ 25 ]. The function of the AVPV kisspeptin neurons in the male
rodent is not clear, but these neurons may be involved in generating the basal pulsa-
tile release of LH via a stimulatory action on GnRH neurons.
In other species, such as the guinea pig, sheep, and rhesus monkey, the preoptic
area (POA) appears not to be the main region responsible for E 2 positive feedback
[ 26 - 30 ]. Thus, it appears that the basal hypothalamus may be suffi cient for main-
taining steroid-mediated positive feedback regulation of GnRH and LH secretion in
these species. Consistent with these fi ndings, kisspeptin neurons within the arcuate
nucleus in guinea pig, sheep, and monkey appear to be involved in E 2 -mediated
positive as well as negative feedback regulation of GnRH neurons [ 31 - 34 ]. The
specifi c kisspeptin neurons within the arcuate nucleus that mediate positive feed-
back regulation of LH remains to be determined, although evidence suggests that a
caudal arcuate population of neurons is involved [ 31 - 34 ]. However, irrespective of
the role of the arcuate nucleus in mediating E 2 positive feedback on LH secretion in
certain species, evidence suggests that the POA is also involved [ 31 , 34 , 35 ].
Importantly, regardless of differential regulation of Kiss1 neurons by E 2 , in all
instances, kisspeptin potently excites GnRH neurons via a phospholipase C (PLC)
signaling pathway (see below).
To further study the role of kisspeptin in the regulation of GnRH neurons and LH
release, kisspeptin analogs with mixed agonist/antagonist activities have been syn-
thesized [ 36 ]. Of these, peptide 234 has primarily antagonist activities in Chinese
Hamster Ovary K1 (CHO-K1) cells expressing Kiss1R and inhibits the kisspeptin

β