Gonadotrophs And GnRh Receptors

Gonadotrophs account for 6-10% of the cells of the normal anterior pituitary (14). Gonadotrophs may be small and round or larger and ovoid and are difficult to identify by morphological criteria. Instead, immunostaining, using specific antibodies for LH-P and FSH-P proteins, is used to identify gonadotrophs. In primates (15), as in rodents (14), the majority of gonadotrophs are bihormonal, i.e., they express both LH-P and FSH-P subunit genes. A small fraction of cells express LH or FSH selectively, and

Testosterone Gonadotroph
Fig. 2. Signaling mechanisms initiated by activation of the gonadotropin-releasing hormone (GnRH) receptor stimulate gonadortopin synthesis and secretion.

some gonadotrophs produce growth hormones, as well as the gonadotropic hormones. However, the biological significance of these observations remains unclear.

GnRH activates gonadotrophs through both short-term and long-term mechanisms that are illustrated in Fig. 2. After reaching the pituitary, GnRH binds to and activates a cell-surface G protein-coupled receptor (GnRH-R) (16). This receptor is a structurally unique member of the seven-transmembrane G protein-linked receptor family that lacks the long C-terminal intracellular tail that is typical of most GPCRs. This tail is important in the rapid desensitization of other GPCRs, whereas downregulation of the GnRH receptor by GnRH is a relatively delayed event occurring over hours rather than minutes. GnRH binding to its receptor facilitates binding of a G protein to the receptor's third intracellular loop. The bound G protein exchanges guanosine 5'-diphosphate (GDP) for guanosine 5'-triphosphate (GTP) and dissociates into its constituent a and Py subunits. The a-subunits are unique to each G protein, whereas the P- and y-subunits of the different G proteins are similar. The dissociated G protein a-subunit activates downstream signaling pathways (17). Gqa, the major G protein that associates with the GnRH-R, activates membrane-associated phospholipase C to hydrolyze membrane phosphoinositides and increases intracellular inositol phosphates (Ips), including inositol triphosphate (Ii,4,5>P3. IP3 rapidly mobilizes calcium from intracellular stores, and voltage-gated calcium channels open, after which extracellular calcium enters the cell (17). The rise in intracellular free calcium is primarily responsible for the immediate LH and FSH release (18). GnRH receptors may also interact with other G proteins.

The long-term stimulatory effects of GnRH are to increase transcription of the genes for the gonadotropin subunits and for the GnRH receptor. These effects occur primarily through liberation of membrane diacylglycerol (DAG) that, in turn, activates protein kinase C (PKC). The subsequent phosphorylation of subfamilies of mitogen-activated protein kinases (MAP kinases), including members of the Extracellular Signal-regulated Kinase (ERK) and JNK families, initiates nuclear translocation of proteins that bind directly to the 5' regulatory regions of the gonadotropin subunit and the GnRH-receptor genes or serve as cofactors for promoter activation (19). Increased intracellular calcium also contributes to the transcriptional GnRH effects (20).

GnRH receptors are upregulated by pulsatile GnRH (21). Accordingly, when pulsatile GnRH secretion increases, as in castration or primary testicular failure, GnRH receptors increase. Gonadotrophs become more responsive to GnRH, and the LH response to GnRH stimulation is amplified (22). With continuous GnRH treatment, on the other hand, GnRH receptors decline, followed by a suppression of LH-P and FSH-P mRNAs. This 'homologous desensitization" of the GnRH-R is regulated by several serine-threonine protein kinases, including protein kinase A (PKA) and PKC, as well as by G protein-coupled receptor kinases (GRKs). GnRH receptors also decline with GnRH deficiency.

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