Estradiol and Kisspeptin Modulation of Gonadotropin-Releasing Hormone (GnRH) Neuronal Excitability

Kisspeptin is a neuropeptide that signals via a Gαq-coupled receptor, GPR54, in GnRH neurons to play a vital role in the modulation of GnRH neuronal excitability, which controls pituitary gonadotropin secretion and ultimately pubertal maturation and fertility (see also Hiroaka and Mori, this volume). GnRH neurons are located in the medial septum, rostral preoptic area, and the ventral mediobasal hypothalamus in higher species (see also Iremonger and Herbison, this volume) and receive synaptic input from kisspeptin neurons that are located in a continuum from the rostral periventricular area to the caudal arcuate nucleus. Kisspeptin neurons are probably the "pacemaker" neurons that depolarize and excite GnRH neurons primarily through the kisspeptin-mediated activation of canonical transient receptor potential channels (TRPCs). Also, the gonadal steroid 17β-estradiol (E2) has both presynaptic and postsynaptic actions on GnRH neurons, but one primary postsynaptic action of E2 is to upregulate the expression of channel transcripts that orchestrate the downstream signaling of kisspeptin in GnRH neurons. These include not only TRPC4 channels, but also low voltage-activated T-type calcium channels and high voltage-activated L-type calcium channel transcripts. In addition, E2 has direct "non-genomic" actions to alter the excitability of GnRH neurons by enhancing ATP-sensitive potassium (KATP) channel activity, which is critical for maintaining the GnRH neurons in a hyperpolarized state for recruitment of T-type calcium channels that are important for burst firing. E2 rapidly modulates the activity of KATP channels via a membrane-initiated signaling (Gαq-protein coupled membrane estrogen receptor) pathway in GnRH neurons (Box 13.1). Therefore, kisspeptin provides a critical excitatory input to GnRH neurons, and E2 modulates the excitability of GnRH neurons by upregulating the downstream targets (channels) and direct membrane actions to facilitate burst firing activity.