Mechanism of GnRH receptor signaling: combinatorial cross-talk of Ca2+ and protein kinase C.

Gonadotropin-releasing hormone (GnRH), the first key hormone of reproduction, is synthesized in the hypothalamus and is released in a pulsatile manner to stimulate pituitary gonadotrope-luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and release. Gonadotropes represent only about 10% of pituitary cells and are divided into monohormonal cells (18% LH and 22% FSH cells) and 60% multihormonal (LH + FSH) cells. GnRH binds to a specific seven transmembrane domain receptor which is coupled to Gq and activates sequentially different phospholipases to provide Ca2+ and lipid-derived messenger molecules. Initially, phospholipase C is activated, followed by activation of both phospholipase A2 (PLA2) and phospholipase D (PLD). Generation of the second messengers inositol 1,4,5-trisphosphate and diacylglycerol (DAG) lead to mobilization of intracellular pools of Ca2+ and activation of protein kinase C (PKC). Early DAG and Ca2+, derived via enhanced phosphoinositide turnover, might be involved in rapid activation of selective Ca(2+)-dependent, conventional PKC isoforms (cPKC). On the other hand, late DAG, derived from phosphatidic acid (PA) via PLD, may activate Ca(2+)-independent novel PKC isoforms (nPKC). In addition, arachidonic acid (AA) which is liberated by activated PLA2, might also support selective activation of PKC isoforms (PKCs) with or without other cofactors. Differential cross-talk of Ca2+, AA, and selective PKCs might generate a compartmentalized signal transduction cascade to downstream elements which are activated during the neurohormone action. Among those elements is the mitogen-activated protein kinase (MAPK) cascade which is activated by GnRH in a PKC-, Ca(2+)-, and protein tyrosine kinase (PTK)-dependent fashion. Transcriptional regulation can be mediated by the activation of transcription factors such as c-fos by MAPK. Indeed, GnRH activates the expression of both c-jun and c-fos which might participate in gene regulation via the formation of AP-1. The signaling cascade leading to gonadotropin (LH and FSH) gene regulation by GnRH is still not known and might involve the above-mentioned cascades. AA and selective lipoxygenase products such as leukotriene C4 also participate in GnRH action, possibly by cross-talk with PKCs, or by an autocrine/paracrine amplification cycle. A complex combinatorial, spatial and temporal cross-talk of the above messenger molecules seems to mediate the diverse effects elicited by GnRH, the first key hormone of the reproductive cycle.