Kisspeptin: Past, Present, and Prologue - Kisspeptin Signaling in Reproductive Biology - page 4

anisms that govern GnRH neurons, the fi nal common pathway through which the
brain regulates reproduction, and put upfront the classical neurotransmitters
(e.g., acetylcholine, norepinephrine, dopamine), certain amino acids (e.g., glutamate
and GABA), as well as a constellation of neuropeptides that regulate GnRH
neurons. The list of neuropeptides implicated in the regulation of GnRH secretion
in mammals boggles the mind—and becomes even more astonishing when we con-
sider those discovered among other nonmammalian vertebrates. Among those with
particular prominence include neuropeptide Y, proopiomelanocortin (and its prod-
ucts), galanin, and the RF amide family—not to mention their extended family of
receptor subtypes. Yet, by the turn of the twenty-fi rst century, many in the neuroen-
docrinology community felt that something was missing. Although neuropharma-
cology and molecular mapping argued persuasively that these neuropeptides play
key regulatory roles in the regulation of GnRH secretion, all the hoot 'n holler didn't
change the fact that knockouts of Npy , Gal , Agrp , Pomc , and the like failed to pro-
duce remarkable reproductive phenotypes. The fi eld of dreams had become parched
under intense illumination and precision mowing. Although it remains true that
redundancy and developmental compensation may excuse the absence of one or
another players, it had become clear that we hadn't really discovered the real secret
how the brain regulates GnRH neurons. Indeed, much of what had been learned in
the 1980s and 1990s was on margin—worthwhile, but no Holy Grail. We still didn't
know how the brain triggers the onset of puberty; we didn't know the identity of
molecular and cellular pathways that allow sex steroids to communicate with GnRH
neurons, (since these cells don't express the appropriate receptors); we had nary a
clue about the mechanisms that link the circadian clock to GnRH neurons and
induce ovulation at a precise time of day, nor how season is perceived by the neuro-
endocrine reproductive axis—not to mention how a tiny network of GnRH neurons
is capable of generating discrete “pulses” that drive LH secretion.
The world as we knew it changed in late 2003, when it was discovered that
mutations in an obscure cancer-related gene that encodes the receptor for kisspeptin
(aka KISS1R / kiss1r or GPR5 / Gpr54 ) cause profound hypogonadotropic hypogo-
nadism in humans and mice—a rare fi nding reported by two separate groups in
papers that launched a thousand ships. Thus began the saga of kisspeptin signaling
in the neuroendocrine regulation of reproduction. Today, almost 10 years and a
1,000 papers later, kisspeptin has emerged as the chargé d ' affaires —providing
impetus, information, and guidance to GnRH neurons, whose ancient role in repro-
duction may more akin to that of a motor neuron—an essential servant but no savant.
If the GnRH neuron is the prima ballerina, certainly the kisspeptin neuron must be
her choreographer. Indeed, we've learned a lot about kisspeptin and reproduction in
the past decade!
Scientists enjoy a wide consensus about many aspects of kisspeptin signaling.
We know that kisspeptin acts through a G q/11 -coupled mechanism to activate GnRH

neurons, which express Kiss1r, by inhibiting A-type and inwardly rectifying K + currents
and activating TRPC currents to induce depolarization and sustained action poten-
tials. We've learned that kisspeptin-expressing neurons reside in many parts of the
brain (and in cells elsewhere in the body) and likely serve many different functions

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