Kisspeptin Excitation of GnRH Neurons - Kisspeptin Signaling in Reproductive Biology - page 110

Chapter 6
Kisspeptin Excitation of GnRH Neurons
Oline K. Rønnekleiv and Martin J. Kelly
Abstract Kisspeptin binding to its cognate G protein-coupled receptor (GPR54,
aka Kiss1R) in gonadotropin-releasing hormone (GnRH) neurons stimulates pep-
tide release and activation of the reproductive axis in mammals. Kisspeptin has
pronounced pre- and postsynaptic effects, with the latter dominating the excitability
of GnRH neurons. Presynaptically, kisspeptin increases the excitatory drive (both
GABA-A and glutamate) to GnRH neurons and postsynaptically, kisspeptin inhibits
an A-type and inwardly rectifying K + (Kir 6.2 and GIRK) currents and activates
nonselective cation (TRPC) currents to cause long-lasting depolarization and
increased action potential fi ring. The signaling cascades and the multiple intracel-
lular targets of kisspeptin actions in native GnRH neurons are continuing to be
elucidated. This review summarizes our current state of knowledge about kisspeptin
signaling in GnRH neurons.
Relationship Between Kisspeptin and GnRH Secretion
Kisspeptin, encoded by the Kiss1 gene, is a key factor in the regulation of reproduc-
tive development and functions [ 1 - 6 ]. The Kiss1 gene encodes a 145 amino acid
protein, which is proteolytically processed to produce a 54 amino acid peptide,
called kisspeptin-54, and several other smaller peptide fragments [ 7 ]. Centrally
administered kisspeptins stimulate GnRH and gonadotropin secretion in prepuber-
tal and adult animals [ 1 , 8 - 11 ]. The central application of kisspeptin induces cFos
immunoreactivity within 1-2 h in more than 85% of GnRH neurons, further sug-
gesting that direct activation of the neurons is responsible for the release of
luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [ 8 ]. As expected,
O. K. Rønnekleiv , Ph.D. ( * ) • M. J. Kelly, Ph.D.
Physiology and Pharmacology, Oregon Health and Science University,
L334, 3181 SW Sam Jackson Park Road , Portland , OR 97239 , USA
e-mail: [e-mail]