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

Abstract

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

Growth Differentiation Factor 9 (GDF9) Forms an Incoherent Feed-forward Loop Modulating Follicle-stimulating Hormone β-Subunit (FSHβ) Gene Expression

“…GnRH induces PACAP expression in the gonadotropes, and the increase in PACAP transcripts is significantly more prominent at a lower pulse frequency (54). Evidence suggests that PACAP may be involved in GnRH pulse frequency-dependent stimulation of FSH␤ expression in L␤T2 cells (55). These extracellular factors constitute a complex regulatory network, which our results suggest need to be considered as an integral extension of intracellular signal processing in controlling gonadotrope responses.…”

Expression of gonadotropin-inhibitory hormone receptors in mouse pituitary gonadotroph LβT2 cells and hypothalamic gonadotropin-releasing hormone-producing GT1-7 cells

“…Although the detailed mechanisms of GnRH pulse frequency-dependent gonadotropin subunit gene expression have not been fully elucidated, the pattern of GnRH receptor expression is one of the causes of this phenomenon. GnRH also regulates the expression of the pituitary adenylate cyclase-activating polypeptide type I receptor within pituitary gonadotroph cells and potentiates the effect of GnRH on gonadotropin subunit gene expression [28]; it is also reportedly involved in the specific regulation of gonadotropin subunits [29]. Thus, GnRH regulates the expression of receptors for other peptides that have effects on gonadotroph cells and probably modulates the synthesis and release of gonadotropin.…”

GnRH-Induced Ca2+ Signaling Patterns and Gonadotropin Secretion in Pituitary Gonadotrophs. Functional Adaptations to Both Ordinary and Extraordinary Physiological Demands

“…There is no a definitive explanation to how GnRH pulses can activate in a different manner gonadotropin subunit gene transcription; nevertheless several routes have been proposed which may contribute to this regulation; one is through the increase on Ca 2+ levels and PKC activation, which as a consequence activated mitogen-activated protein kinase (MAPK) cascade, culminating in an activation of extracellular-signal-regulated kinase (ERK) 1/2, cJun NH2-terminale kinase (JNK), p38 MAPK, and ERK 5 (76–80), it is also believe that the rise in [Ca 2+ ] i , activates a calcium/calmodulin-dependent kinase II (CAMK2), whose autophosphorylation could be important in transmitting Ca 2+ pulse frequency and amplitude signals, as fast and high-amplitude Ca 2+ influxes, which results in greater and/or sustained Ca 2+ /CALM1 levels (79, 81) (Figure 1). GnRH pulses at lower frequency selectively increase the expression of PACAP and its receptor (PAC1-R) in gonadotrophs (82), where they subsequently stimulate the synthesis of gonadotropin subunits (83). …”