New concepts in GnRH receptor function

Hypothalamic GnRH is the central regulator of the reproductive system through the stimulation of LH and FSH. These effects are mediated through a single type of GnRH receptor in gonadotropes that signals predominantly via Gq to elevate intracellular Call and activate selective PKC isoforms in particular PKGdelta and PKCepsilon. Over the past decade a considerable body of research has demonstrated non-pituitary effects of GnRH and analogues in the central and peripheral nervous system, peripheral reproductive tissues and in reproductive cancer cells. Most of these effects exhibit different pharmacology and intracellular signalling compared with that in gonadotropes. This suggested that these effects may be mediated via a second type of GnRH receptor. We cloned this Type II receptor from amphibians and a Type 11 homologue was cloned from non-human primates. However, we established that the human homologue had a frame shaft and stop codon such that a Type II receptor could not be translated. Similar disruptions or deletions exist in the chimp, bovine, ovine and rodent genes. Our studies have then demonstrated that the atypical pharmacology and signalling in human tumour cells can be displayed by the conventional pituitaiy Type I receptor and that this is determined by the intracellular protein environment. A different spectrum of GnRH agonists as well as certain antagonists stabilise the Type I receptor in a conformation which favours Gi activation as opposed to the pituitaiy Gq effects. Gi activation results in p38 and JNK activation leading to apoptosis. We have also demonstrated that these effects are unique to the Type I GnRH receptor and not other GPCRs due to the absence of the carboxy terminal tail and lack of rapid desensitisation. Recognition of these differential Gi and Gq effects have enabled us to identify agonists which are preferential Gi activators, antagonists which only inhibit Gq, and antagonists which inhibit Gq and activate Gi. These discoveries allow the development of more specific GnRH analogues which will selectively target gonadotropes, tumour cells, neurones, immune cells and peripheral cells in the reproductive tissues. In addition to the activation Of Gq and Gi, the GnRH Type I receptor is capable of activating Gs and modulating the function of gonadotropes and GnRH neuronal cell lines. Recently we have delineated a number of signalling Pathways which are mediated by monomeric G-proteins, focal adhesion protein complexes, with and without interaction with extracellular matrix proteins, and intracellular interaction with c-Src, PYK2, Grb2, SOS, DGK-zeta, ERK1/2, p38 and JNK to gonadotropin submint (alpha, LHbeta and FSHbeta) gene transcriptions, cyloskeletal reorganisation and cell adhesion. In addition, GnRH activation of the focal adhesion protein complexes can induce androgen receptor (AR) translocation to the nucleus through the androgen activating protein Hic-5. However, the translocated AR is not transcriptionally active such that GnRH ablates the effects of androgen on gene transcription.