Molecular mechanisms of gonadotropin-releasing hormone signaling: integrating cyclic nucleotides into the network

Abstract

Gonadotropin-releasing hormone (GnRH) is the primary regulator of mammalian reproductive function in both males and females. It acts via G-protein coupled receptors on gonadotropes to stimulate synthesis and secretion of the gonadotropin hormones luteinizing hormone and follicle-stimulating hormone. These receptors couple primarily via G-proteins of the Gq/ll family, driving activation of phospholipases C and mediating GnRH effects on gonadotropin synthesis and secretion. There is also good evidence that GnRH causes activation of other heterotrimeric G-proteins (Gs and Gi) with consequent effects on cyclic AMP production, as well as for effects on the soluble and particulate guanylyl cyclases that generate cGMP. Here we provide an overview of these pathways. We emphasize mechanisms underpinning pulsatile hormone signaling and the possible interplay of GnRH and autocrine or paracrine regulatory mechanisms in control of cyclic nucleotide signaling.

Keywords: ERK; G-proteins; GnRH; PACAP; adenylyl cyclase; guanylyl cyclase; natriuretic peptide; phospholipase C.

Figure 1

GnRH receptor signaling networks. (A) Illustrates a generic signaling network in which a GPCR activates two heterotrimeric G-proteins (G1 and G2) which activate their cognate effectors (E1 and E2). These directly or indirectly activate down-stream effectors that influence a range of target proteins including transcription factors (TF1-4). The transcription factors then act (typically in combination) to influence expression of numerous target genes. Note that the network has multiple sites for divergence and convergence. (B) Shows a GnRH signaling network with the same architecture; The GnRHR activates Gs and Gq leading to activation of adenylyl cyclase (AC) and phospholipase C (PLC). AC generates cAMP, stimulating PKA which activates the transcription factor CREB. PLC leads to activation of PKC, driving activation of ERK and of ERK-dependent transcription via Sf-1 and Egr-1. It also elevates the cytoplasmic Ca²⁺ concentration, driving activation of calmodulin and its targets, including calcineurin which leads to activation of the Ca²⁺-dependent transcription factor NFAT. This cartoon is clearly a vast oversimplification as important effectors (including calmodulin-dependent kinases, JNK, p38, and nitric oxide synthase) are not included. Perhaps more importantly, it also excludes signal dynamics and heterologous regulation, both of which are important for control of gonadotropes. A simple example of the latter is given in (C) which includes the PAC1 receptor as a mediator of PACAP-stimulated AC activation, and the NPRB receptor as a mediator of CNP-stimulated cGMP accumulation and consequent protein kinase G (PKG) activation. GnRH can cause PKC-mediated inhibition of PACAP-stimulated cAMP accumulation and of CNP-stimulated cGMP accumulation (as indicated by the dashed red lines), raising the possibility that its predominant effect is actually inhibition of these pathways in gonadotropes exposed to autocrine or paracrine stimulation of PAC1 and NPRB. Finally, when considering signal dynamics, it is important to recognize: (a) that GnRH is secreted in pulses, (b) that the responses illustrated have distinct kinetics, (c) that the kinetics of convergent pathways are important determinants of GnRH pulse frequency-response relationships, and (d) that GnRH influences the expression of many genes encoding components of the GnRHR signaling pathways, with transcription-dependent feedback loops supporting an adaptive signaling network.