Mechanisms of GnRH Action: Interactions Between GnRH-Stimulated Calcium-Phospholipid Pathways Mediating Gonadotropin Secretion

Abstract

Hypothalamic regulation of gonadotropin secretion is exerted through receptor-mediated actions of gonadotropin-releasing hormone (GnRH) on pituitary gonadotropes. In rat pituitary cells, the GnRH receptor consists of two binding components of molecular weight 53,000 and 42,000 as revealed by photoaffinity labelling techniques (Iwashita and Catt, 1985). As with all peptide hormones, GnRH-receptor binding leads to activation of intracellular “second messenger” systems that culminate in the release of gonadotropins. The regulation of luteinizing hormone (LH) secretion by GnRH has been extensively studied in cultured rat anterior pituitary cells and in gonadotrope-enriched fractions prepared by centrifugal elutriation for the identification of specific effects of GnRH on the activation of second messenger systems. Although both cAMP and cGMP levels are increased in pituitary cell cultures following GnRH stimulation (for review see Conn et al., 1981), cAMP (Sen and Menon, 1979) and cGMP (Naor and Catt, 1980) do not appear to mediate acute LH responses to the releasing peptide. GnRH stimulation of LH release is a Ca²⁺ -dependent process (Conn et al., 1981; Conn, 1986). Arachidonic acid (AA) and its lipoxygenase products, as well as the activation of protein kinase C, a Ca²⁺ - and phospholipid-dependent enzyme, have been implicated as mediators of GnRH-induced LH secretion (for reviews see Catt et al., 1984, 1985). More recently, GnRH-stimulated hydrolysis of phosphoinositides has also been shown to participate in the mechanism of GnRH action (Catt et al., 1984, 1985; Schrey, 1985). In this article, results from recent investigations into the mechanisms of action of GnRH, as well as evidence suggesting that the LH response to GnRH requires the coordination of several intracellular messenger systems, will be presented and discussed.