Kisspeptin Excitation of GnRH Neurons - Kisspeptin Signaling in Reproductive Biology - page 112

response by 93%, with an IC50 of 7 nM [ 36 ]. This compound also has a binding
affi nity of 2.7 nM for Kiss1R stably expressed in CHO-K1 cells. Peptide 234 sub-
sequently has been found to inhibit kisspeptin-induced GnRH neuronal fi ring
in vitro, whereas in vivo treatment with the peptide attenuates kisspeptin-induced
LH release in intact males [ 36 ]. Moreover, peptide 234 attenuates the castration rise
in plasma LH levels in mouse and rat, and reduces pulsatile LH release in the ovari-
ectomized ewe and rat [ 36 , 37 ]. Also, in ovariectomized monkeys, peptide 234
attenuates pulsatile release of GnRH [ 36 ]. Collectively, these data support the con-
cept that kisspeptin neurons (in the arcuate nucleus?) are involved in stimulating
GnRH and LH release following gonadectomy.
Thus, the estrogen-mediated “negative” feedback inhibition of post-castration
GnRH and LH release may be via the differential release of kisspeptin/opioid pep-
tides since this group of arcuate neurons also co-localizes dynorphin [ 38 , 39 ].
Although there is a robust

μ -opioid receptor-mediated inhibition of GnRH neurons

in guinea pig [ 40 ], a κ -opioid-mediated effect has not been demonstrated.

Kisspeptin Activation of Kiss1R

Kisspeptin-54 has been identifi ed as the endogenous ligand of the orphan G protein-
coupled receptor, GPR54 [ 7 , 41 ], also known as Kiss1R. In addition to kisspeptin-54,
the smaller peptide fragments derived from the precursor protein (e.g., kisspeptin
14, 13, and 10) all have biological activity at Kiss1R [ 7 , 42 ]. These peptides bind
with low nanomolar affi nities to rat and human Kiss1R expressed in Chinese ham-
ster ovary K1 cells and stimulate PIP2 hydrolysis, Ca 2+ mobilization, arachidonic
acid release, extracellular signal-regulated protein kinase 1 (ERK1), ERK2, and p38
MAP kinase phosphorylation [ 7 ]. In mammals, Kiss1R is expressed both in the
pituitary and in GnRH neurons [ 7 , 8 , 11 , 12 ]. However, as stated above, evidence
suggests that the stimulation of gonadotropin secretion by kisspeptin is via direct
activation of GnRH neurons and not pituitary gonadotropes [ 1 , 8 - 10 , 43 ]. Although
multiple actions of kisspeptin have been identifi ed (see below), all of the signaling
pathways have not been elucidated.

Kisspeptin Activation of Kiss1R in GnRH Neurons:
Downstream Signaling Pathways

To date, kisspeptin is the most potent and effi cacious neuropeptide/neurotransmitter
to excite native GnRH neurons [ 44 - 49 ]. In most studies, kisspeptin is reported to
depolarize and excite the vast majority (75-90%) of GnRH neurons (Fig. 6.1 ),
which correlates with the expression of Kiss1R in the majority of GnRH neurons
[ 8 , 12 , 14 , 50 ]. However, Dumalska et al. found a lower percentage of GnRH