Kisspeptin neurons mediate reflex ovulation in the musk shrew ( Suncus murinus )

Abstract

The present study investigated whether kisspeptin-G protein-coupled receptor 54 (GPR54) signaling plays a role in mediating mating-induced ovulation in the musk shrew (Suncus murinus), a reflex ovulator. For this purpose, we cloned suncus Kiss1 and Gpr54 cDNA from the hypothalamus and found that suncus kisspeptin (sKp) consists of 29 amino acid residues (sKp-29). Injection of exogenous sKp-29 mimicked the mating stimulus to induce follicular maturation and ovulation. Administration of several kisspeptins and GPR54 agonists also induced presumed ovulation in a dose-dependent manner, and Gpr54 mRNA was distributed in the hypothalamus, showing that kisspeptins induce ovulation through binding to GPR54. The sKp-29-induced ovulation was blocked completely by pretreatment with a gonadotropin-releasing hormone (GnRH) antagonist, suggesting that kisspeptin activates GnRH neurons to induce ovulation in the musk shrew. In addition, in situ hybridization revealed that Kiss1-expressing cells are located in the medial preoptic area (POA) and arcuate nucleus in the musk shrew hypothalamus. The number of Kiss1-expressing cells in the POA or arcuate nucleus was up-regulated or downregulated by estradiol, suggesting that kisspeptin neurons in these regions were the targets of the estrogen feedback action. Finally, mating stimulus largely induced c-Fos expression in Kiss1-positive cells in the POA, indicating that the mating stimulus activates POA kisspeptin neurons to induce ovulation. Taken together, these results indicate that kisspeptin-GPR54 signaling plays a role in the induction of ovulation in the musk shrew, a reflex ovulator, as it does in spontaneous ovulators.brain | copulation | Kiss1r | metastin | ovary

Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization

“…Clinically difficult egg collection was Conversely, peripheral administration of kisspeptin triggers egg maturation in female rats primed with gonadotropins (28). In addition, exogenous administration of kisspeptin induces ovulation in the musk shrew (26), rats (28), and sheep (29). In keeping with this, human studies demonstrate that kisspeptin stimulates LH release most potently during the preovulatory phase of the menstrual cycle (i.e., the time of the cycle just prior to ovulation) in females with regular, normal menstrual cycles (18,21,30).…”

“…It is also important to consider the safety of kisspeptin in IVF treatment. Kisspeptin is a naturally occurring peptide hormone that plays a physiological role in triggering ovulation (25)(26)(27)(28)(29). Reassuringly, circulating levels of kisspeptin-54 rise dramatically, up to 7,000-fold, during normal human pregnancy and remain elevated for the duration of a normal nine-month pregnancy (33).…”

“…Recent evidence from animals suggests that kisspeptin may activate the LH surge required for egg maturation and ovulation. In rodents, the proestrus LH surge is abolished by a specific monoclonal antibody that blocks the actions of hypothalamic kisspeptin (26), and the LH surge has been observed to be absent in transgenic mice null for kisspeptin or its receptor (27).…”

The roles of kisspeptin and gonadotropin inhibitory hormone in stress-induced reproductive disorders

“…Indeed, subsequent studies have shown that kisspeptin stimulates GnRH secretion via GPR54 on GnRH neurons [48][49][50]. The amino acid sequence of kisspeptin, especially the C-terminal 10-amino acid sequence, is well conserved in most mammals [51][52][53][54][55][56][57]. Hypothalamic kisspeptin neurons are mainly located in the anterior and posterior nuclei; i.e., the anteroventral periventricular nucleus (AVPV)/preoptic area (POA) and arcuate nucleus (ARC) [55,56,[58][59][60][61][62][63][64].…”

“…The amino acid sequence of kisspeptin, especially the C-terminal 10-amino acid sequence, is well conserved in most mammals [51][52][53][54][55][56][57]. Hypothalamic kisspeptin neurons are mainly located in the anterior and posterior nuclei; i.e., the anteroventral periventricular nucleus (AVPV)/preoptic area (POA) and arcuate nucleus (ARC) [55,56,[58][59][60][61][62][63][64]. Kiss1 mRNA expression in the AVPV/POA is increased in the afternoon during proestrus and is also upregulated by the administration of estrogen, whereas Kiss1 mRNA expression in the ARC is decreased by the administration of estrogen [61,63,[65][66][67].…”