MECHANISM OF GNRH RECEPTOR SIGNALING - COMBINATORIAL CROSS-TALK OF CA2-KINASE-C( AND PROTEIN)

Gonadotropin-releasing hormone (GnRH), the first key hormone of reprod uction, is synthesized in the hypothalamus and is released in a pulsat ile manner to stimulate pituitary gonadotrope-luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and release. Gonadot ropes 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 r eceptor which is coupled to Gq and activates sequentially different ph ospholipases to provide Ca2+ and Lipid-derived messenger molecules. In itially, phospholipase C is activated, followed by activation of both phospholipase A(2) (PLA(2)) and phospholipase D (PLD). Generation of t he second messengers inositol 1,4,5-trisphosphate and diacylglycerol ( DAG) lead to mobilization of intracellular pools of Ca2+ and activatio n of protein kinase C (PKC). Early DAG and Ca2+, derived via enhanced phosphoinositide turnover, might be involved in rapid activation of se lective Ca2+-dependent, conventional PKC isoforms (cPKC). On the other hand, late DAG, derived from phosphatidic acid (PA) via PLD, may acti vate Ca2+ independent novel PKC isoforms (nPKC). In addition, arachido nic acid (AA) which is liberated by activated PLA(2), might also suppo rt selective activation of PKC isoforms (PKCs) with or without other c ofactors. Differential cross-talk of Ca2+, AA, and selective PKCs migh t generate a compartmentalized signal transduction cascade to downstre am 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-, Ca2+-, and protein tyrosine kina se (PTK)-dependent fashion. Transcriptional regulation can be mediated by the activation of transcription factors such as c-fos by MAPK. ind eed, GnRH activates the expression of both c-jun and c-fos which might participate in gene regulation via the formation of AP-1. The signali ng cascade leading to gonadotropin (LH and FSH) gene regulation by GnR H is still not known and might involve the above-mentioned cascades. A A and selective lipoxygenase products such as leukotriene C-4 also par ticipate in GnRH action, possibly by cross-talk with PKCs, or by an au tocrine/paracrine amplification cycle. A complex combinatorial, spatia l and temporal cross-talk of the above messenger molecules seems to me diate the diverse effects elicited by GnRH, the first key hormone of t he reproductive cycle. (C) 1998 Academic Press.