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It is very likely that the primary role of kisspeptin/Kiss1r signaling in the GnRH
pulse generation mechanism is to transmit volleys of action potentials from the
pulse generator to GnRH neurons and regulate pulsatile GnRH secretion at the level
of the ME. Several lines of evidence support this notion. First, in monkeys, kiss-
peptin is secreted into the ME episodically and is temporally associated with pulsa-
tile GnRH secretion [
108
]. Second, kisspeptin stimulates GnRH release from the
ME in vivo [
108
] and in vitro [
74
,
75
,
109
], potentially acting via Kiss1r [
109
].
Third, administration of a kisspeptin antagonist directly into the ME suppresses
pulsatile GnRH release [
110
].
Interaction of NKB and Kisspeptin Signaling
Human genetic studies [
89
,
90
,
111
,
112
] indicate that kisspeptin and NKB signaling
play pivotal roles in the control of reproduction by facilitating GnRH secretion.
In concert, it has been demonstrated in a variety of species that activation of Kiss1r
[
113
] or NK3R [
58
-
60
,
114
-
117
] increases LH secretion. Moreover, it has been
shown that administration of antagonists for either Kiss1r [
75
,
110
] or NKB recep-
tor [
60
,
118
] suppresses LH secretion. Their similar physiological characteristics
and concomitant existence in KNDy neurons suggest an intimate association
between kisspeptin and NKB signaling.
Recently it has been demonstrated that the blockade of kisspeptin/Kiss1r signaling
by Kiss1r desensitization [
115
] or in Kiss1r KO mice [
116
] abrogates the stimulatory
action of senktide on LH secretion, whereas the block of NKB/NK3R signaling
by NK3R desensitization does not affect the ability of kisspeptin to stimulate LH
secretion [
115
]. We have observed in goats that the blockade of kisspeptin/Kiss1r
signaling completely eliminates LH pulses without affecting the MUA volley [
103
],
whereas the occurrences of the MUA volley and LH pulses are concomitantly post-
poned after the injection of NK3R antagonist (Wakabayashi et al., unpublished data).
Furthermore, GnRH neurons possess Kiss1r [
75
,
104
,
119
] but not NK3R [
58
,
66
],
but see Krajewski et al. [
120
], and NK3R agonists have no effect on electrophysio-
logical activities of GnRH neurons in vitro [
58
]. Thus, it is plausible to conclude that
NKB/NK3R signaling is upstream from kisspeptin/Kiss1r signaling, and that the
activation of NK3R stimulates, via kisspeptin/Kiss1r signaling, a discharge of GnRH,
and thus LH [
59
,
115
-
117
].
We reported that icv administration of NKB induced a distinct MUA volley, with
an accompanying LH pulse, in P-treated OVX goats, whereas the association of the
MUA volley and LH pulse was ambiguous in some instances in OVX and E2-treated
OVX goats, and overall LH secretion was reduced by a high dose (but not a low
dose) of NKB [
52
]. However, with the latter, the initial event after NKB treatment
was a discharge of LH, which was followed by a gradual decline of basal LH levels
(Fig.
14.4a
). In those animals with reduced LH secretion, several MUA volleys that
had an extraordinarily shorter intervolley interval were induced, and there was a
slight pause before the normal spontaneous MUA volley were reestablished.
We assume that this pause resulted in an extended decline of basal LH levels, leading
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