Biology Reference
In-Depth Information
Introduction (Why Study Neurokinin B in a Kisspeptin Setting?)
Perpetuation of the species is an essential, but extremely energy costly, endeavor for
most animals—especially for mammals [
1
,
2
]. For this reason, it is not surprising that
a vast array of neurotransmitters and endocrine factors are devoted to the precise con-
trol of the gonadotropic axis and, hence, translate the information of environmental and
internal cues into a specifi c timing and pattern of gonadotropin-releasing hormone
(GnRH) release. A key aspect that deserves to be emphasized is the incapability of
GnRH neurons to show a direct response to some important modulators of reproduc-
tive function, e.g., the negative feedback of sex steroids [
3
,
4
]. In recent years,
Kiss1
neurons have been shown to be—directly or indirectly—receptive to numerous regula-
tory cues, including sex steroids and metabolic and circadian factors [
5
]. This has
placed kisspeptin in the spotlight to play a major role as a regulator of GnRH release.
Yet, it is conceivable that such a critical function for the species as reproduction cannot
rely exclusively on a single molecule (kisspeptin) and, hence, a number of essential
“fi ne-tuners” and “fail-safes” might exist to ensure reproductive success. Indeed, in
2009, the endocrine community witnessed the emergence of neurokinin B (NKB) as a
critical player in the control of gonadotropin release [
6
]. In another example of reverse
translational research—suitably called “from bedside to benchside”—human genetic
studies revealed that patients bearing inactivating mutations in the gene encoding NKB
(
TAC3
) or its receptor, neurokinin 3 receptor (NK3R, encoded by
TACR3
), displayed
hypogonadotropic hypogonadism and closely resembled the phenotype of patients
with loss-of-function mutations in the genes that encode kisspeptin (
KISS1
) and the
kisspeptin receptor (
KISS1R
, also known as
GPR54
) [
6
-
13
]. Some of these fi ndings
have also been partially recapitulated in
Tacr3
null mice [
14
], indicating that the NKB/
NK3R system plays a role in the control of gonadotropin secretion in different species.
Altogether, given the clear parallelism in the reproductive phenotype of humans (and
mice) suffering from congenital inactivation of the kisspeptin/Kiss1r or the NKB/
NK3R systems, it is conceivable that the actions of these two neuroendocrine systems
interact to control GnRH release. As a result, signifi cant efforts in the fi eld have been
recently devoted to puzzle out this interaction in what may constitute a nodal regula-
tory center in the control of reproductive function. This chapter intends to offer a con-
cise overview of the latest achievements in the characterization of the reproductive
facet of the NKB/NK3R system, with attention paid to the implications for the central
mechanisms that govern GnRH release.
The NKB/NK3R System: Structure and Distribution
in the Brain
Neurokinin B
NKB belongs to the tachykinin family of peptides that initially included the neuro-
peptides substance P (SP), neurokinin A (NKA), and NKB and more recently, endo-
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