GnRH-induced PACAP and PAC1 receptor expression in pituitary gonadotrophs: A possible role in the regulation of gonadotropin subunit gene expression

Biology of Reproduction

Purwana

Miyazaki

2013

Self Cite

The pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are mainly under the control of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates male and female gonadal function. GnRH is released in a pulsatile manner from the hypothalamus, and the frequency of GnRH pulses determines the dominance of output of LH and FSH from pituitary gonadotrophs. That is, more rapid pulses of GnRH preferentially increase synthesis and secretion of LH, whereas FSH is preferentially stimulated by slower GnRH pulses. The detailed mechanisms underlying this phenomenon remain unknown. Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally identified as a hypothalamic activator of cAMP production in pituitary cells. PACAP is produced within the pituitary gonadotroph as well as in the central nervous system. PACAP stimulates gonadotropin alpha-, LHbeta-, and FSHbeta-subunits as well as receptors for GnRH in the pituitary gonadotropin-secreting cells. In addition, its own receptor, PACAP type I receptor (PAC1R), is also regulated by PACAP in gonadotrophs. GnRH stimulates expression of PACAP as well as PAC1R, and lower frequencies of GnRH pulses preferentially increase PACAP and PAC1R expression in gonadotrophs. Increasing concentrations of PACAP further increase the levels of gonadotropin subunit and that increasing amounts of PAC1R in gonadotrophs potentiates the effects of PACAP or GnRH on gonadotropin subunit expression. In addition, we have observed that GnRH-increased FSHbeta-subunit expression was prevented in the presence of PAC1R antagonist. These observations suggest the involvement of locally produced PACAP and its PAC1R in the differential regulation of specific gonadotropin subunit expression by pulsatile GnRH stimulation. Here, we review the possible involvement of PACAP and its PAC1R in gonadotropin control on the basis of our observations with gonadotroph cell lines.follicle-stimulating hormone (FSH/FSH receptor), gonadotropinreleasing hormone (GnRH/GnRH receptor), luteinizing hormone (LH/LH receptor), neuroendocrinology, PACAP

Section: Potential Roles Of Pacap In Gnrh Pulse Frequency-dependent Gmentioning

confidence: 99%

Section: Potential Roles Of Pacap In Gnrh Pulse Frequency-dependent Gmentioning

confidence: 99%

Possible Role of PACAP and Its PAC1 Receptor in the Differential Regulation of Pituitary LHbeta- and FSHbeta-Subunit Gene Expression by Pulsatile GnRH Stimulation1

Biology of Reproduction

Purwana

Miyazaki

2013

Self Cite

“…GnRH can stimulate PACAP expression in the primary cultures of pituitary gonadotrophs as well as in the gonadotrophic cell line LbT2 [50,51]. GnRH also increases PAC1R expression [52].…”

Section: Gonadotropin Secretion From Pituitary Gonadotrophsmentioning

confidence: 99%

“…Expression of the LHb-subunit is optimally stimulated at a relatively high cell surface density of GnRHR, whereas FSHb gene expression is favored at a low density of GnRHR [53]. Increasing amounts of PAC1R in the cells potentiate the effects of PACAP on both LHb- and FSHb-subunit gene expression [51]. Furthermore, increasing the density of cell surface PAC1R potentiates the effect of GnRH on both gonadotropin subunits [54] (Figure 2).…”

Section: Gonadotropin Secretion From Pituitary Gonadotrophsmentioning

confidence: 99%

Interactions between Two Different G Protein-Coupled Receptors in Reproductive Hormone-Producing Cells: The Role of PACAP and Its Receptor PAC1R

Oride

Hara

et al. 2016

IJMS

Self Cite

Gonadotropin-releasing hormone (GnRH) and gonadotropins are indispensable hormones for maintaining female reproductive functions. In a similar manner to other endocrine hormones, GnRH and gonadotropins are controlled by their principle regulators. Although it has been previously established that GnRH regulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—both gonadotropins—from pituitary gonadotrophs, it has recently become clear that hypothalamic GnRH is under the control of hypothalamic kisspeptin. Prolactin, which is also known as luteotropic hormone and is released from pituitary lactotrophs, stimulates milk production in mammals. Prolactin is also regulated by hypothalamic factors, and it is thought that prolactin synthesis and release are principally under inhibitory control by dopamine through the dopamine D2 receptor. In addition, although it remains unknown whether it is a physiological regulator, thyrotropin-releasing hormone (TRH) is a strong secretagogue for prolactin. Thus, GnRH, LH and FSH, and prolactin are mainly regulated by hypothalamic kisspeptin, GnRH, and TRH, respectively. However, the synthesis and release of these hormones is also modulated by other neuropeptides in the hypothalamus. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a hypothalamic peptide that was first isolated from sheep hypothalamic extracts based on its ability to stimulate cAMP production in anterior pituitary cells. PACAP acts on GnRH neurons and pituitary gonadotrophs and lactotrophs, resulting in the modulation of their hormone producing/secreting functions. Furthermore, the presence of the PACAP type 1 receptor (PAC1R) has been demonstrated in these cells. We have examined how PACAP and PAC1R affect GnRH- and pituitary hormone-secreting cells and interact with their principle regulators. In this review, we describe our understanding of the role of PACAP and PAC1R in the regulation of GnRH neurons, gonadotrophs, and lactotrophs, which are regulated mainly by kisspeptin, GnRH, and TRH, respectively.

“…ADCYAP1 is also produced within the pituitary gland and works as a paracrine/ autocrine factor [44]. We recently reported that Adcyap1 gene expression in LbT2 cells was increased predominantly by lower frequency GnRH pulses and that increasing concentrations of ADCYAP1 proportionately increased gonadotropin subunit expression levels [45]. The detailed mechanisms for GnRH pulse frequency-dependent Lhb and Fshb subunit gene expression remain complex and require further elucidation.…”

Section: Dusp1 Induction By Pulsatilementioning

confidence: 99%

Induction of Dual-Specificity Phosphatase 1 (DUSP1) by Pulsatile Gonadotropin-Releasing Hormone Stimulation: Role for Gonadotropin Subunit Expression in Mouse Pituitary LbetaT2 Cells1

Purwana

Biology of Reproduction

Mijiddorj

et al. 2011

Self Cite

In pituitary gonadotrophs, GnRH induces expression of the mitogen-activated protein kinases (MAPK3/1) dephosphorylating enzyme, dual-specificity phosphatase 1 (DUSP1). Here we examined DUSP1 expression levels following pulsatile GnRH stimulation of the LbetaT2 gonadotroph cells. DUSP1 expression was increased more prominently following high-frequency (every 30 min) GnRH pulse stimulation (7.02- ± 1.47-fold) than low-frequency (every 120 min) GnRH pulses (2.68- ± 0.09-fold). With high-frequency GnRH pulses, DUSP1 expression increased by 2.89- ± 0.32-fold 2 h after GnRH pulse initiation (four 5-min pulses). DUSP1 expression was not induced following lower frequency GnRH pulses, even when the GnRH concentration was increased. Under high-frequency conditions, MAPK3/1 phosphorylation was observed 10 min after the GnRH pulse and decreased to basal levels after 25 min. However, MAPK3/1 dephosphorylation did not occur concurrently with DUSP1 expression. Overexpression of MAP3K1, a kinase upstream of MAPK3/1, increased both the Lhb and the Fshb subunit promoter activities, which could be completely inhibited by cotransfection with DUSP1-expressing vectors. Serum response factor (Srf) promoter activities induced by MAP3K1 were also prevented by DUSP1 overexpression, confirming that MAPK3/1 has an important role in gonadotropin subunit gene expression. Both high- and low-frequency GnRH pulse stimulation failed to increase the Lhb and Fshb subunit gonadotropin gene expression levels upon DUSP1 overexpression. Our study demonstrates that DUSP1 is specifically expressed following high-frequency GnRH pulses and that this effect may participate in the differential regulation of gonadotropin subunit expression in association with MAPK3/1 phosphorylation.