br GnRH receptor expression is
GnRH receptor expression is altered within GnRH neuronal cells Kisspeptin failed to stimulate GnRH expression in our line of GT1-7 cells. Instead, we have found that kisspeptin increased the expression of the GnRH receptor in these Irinotecan HCl Trihydrate (Sukhbaatar et al., 2013). Based on the results of experiments using pFC-MEKK and pFC-PKA cells, both of which overexpress constitutively active MEKK and protein kinase A (PKA), we speculated that both ERK and PKA activation are necessary to induce GnRH receptor expression (Kanasaki et al., 2013). Pituitary adenylate cyclase-activating polypeptide (PACAP) also increases the expression of GnRH receptors in GT1-7 cells. PACAP was first isolated from an extract of ovine hypothalamus based on its ability to stimulate cAMP accumulation in pituitary cells (Miyata et al., 1989). PACAP and its receptors are distributed throughout the central nervous system as well as in peripheral organs, and PACAP plays an important role as a multifunctional peptide (Vaudry et al., 2009). Furthermore, combined stimulation with kisspeptin and PACAP potentiated their individual effects on the expression of GnRH receptors in GT1-7 cells (Kanasaki et al., 2013). These observations suggest the possibility that GnRH-producing cells are influenced by hypothalamic neuropeptides, such as kisspeptin or PACAP, which modulate their ability to synthesize and secrete GnRH by changing the expression level of the GnRH receptor. It is still unclear how the changes in GnRH receptor expression level within the GnRH-producing neurons affect their GnRH-producing ability, but a recent study using GT1-7 cells demonstrated that ER signaling directly interacted with GnRH receptors (Chason et al., 2015). In addition, based on experiments using GT1-7 or cultured fetal hypothalamic cells, it was reported that characteristic pulsatile secretion was dependent on an autocrine interaction between GnRH and its receptor expression (Krsmanovic et al., 1999, Martinez-Fuentes et al., 2004). GnRH-producing cells respond to GnRH (Neithardt et al., 2006, Shah et al., 2006) and are involved in the control of GnRH expression (Chason et al., 2015, Larco et al., 2015). These findings suggest that the GnRH-producing ability of GnRH neurons is influenced by their density of GnRH receptors.
The neurotransmitter γ-aminobutyric acid (GABA) is a modulator of GnRH neurons. GABA inhibits the stimulatory effect of E2 on GnRH neurons and induces a significant decrease in their tone prior to the LH surge (Jackson and Kuehl, 2002, Smith and Jennes, 2001). GABA neurons express ERα, which GnRH neurons lack, and they are sensitive to E2. GABAergic neuronal synapses terminate on GnRH neurons (Leranth et al., 1985), which possess functional GABAA receptors (Pape et al., 2001, Spergel et al., 1999). GABA predominantly exerts its inhibitory action on GnRH neurons, which has been observed in rodents and sheep. For example, application of a GABAA receptor antagonist increases LH release (Adler and Crowley, 1986, Ferreira et al., 1998). On the other hand, stimulatory effects of GABAA on GnRH neurons were also reported (Moenter and DeFazio, 2005, Yin et al., 2008). GT1-7 cells also express functional GABAA receptors (Garyfallou et al., 2006). GABAA receptors are multimeric proteins that are composed of five subunits from a repertoire of several groups of proteins (α, β, γ, δ, ε, θ, and π). Although the majority of GABAA receptors in the brain are composed of α, β, and γ subunits, less abundant populations of GABAA receptor contain the δ subunit (Brown et al., 2002). The δ-subunit-containing α4β3δ-GABAA receptor (δ-GABAA receptor) was found in extra-synaptic sites and activates inward currents in GnRH neurons and controls neuronal excitability (Bhattarai et al., 2011). Interestingly, we found that stimulation of GT1-7 cells with a δ-GABAA receptor agonist, DS1 (Wafford et al., 2009), decreased GnRH mRNA expression, whereas GnRH receptor expression was increased by DS1 (Sukhbaatar et al., 2015). Why this δ-GABAA receptor agonist decreases GnRH production in GT1-7 cells in spite of increasing the GnRH receptor expression is not known, but we speculate that GABA could modulate GnRH-producing neuronal cells through the δ-GABAA receptor and deplete their GnRH content by modulating gene expression and secretory functions in association with their GnRH receptor expression.