Secretogranin II–derived peptide secretoneurin differentially stimulates luteinizing hormone secretion by age and sex in ex vivo murine pituitaries

Secretoneurin (SN) is a small, bioactive proteolytic product of secretogranin II (SCG2), a chromogranin protein involved in secretory vesicle packaging. SCG2 co-aggregates with luteinizing hormone (LH) in pituitary gonadotrope secretory granules and thus has long been associated with GnRH-regulated LH secretion. Previously, the SCG2-derived peptide SN has been identified as a regulator of LH production and secretion in fish and a murine gonadotrope-like cell line (LβT2). Though high levels of SCG2/SN are present in the mammalian pituitary, the role of pituitary SN has not been identified in mammals. It is further unknown if pituitary SN function varies with age and sex. Here, we identify a decrease in levels of precursor SCG2, and a trend towards increased levels of SN throughout postnatal developmental, particularly in females, following the onset of puberty. Additionally, proteomic and bioinformatic analyses of adult male and female pituitaries revealed protein-protein interactions between SCG2 and various peptides, many associated with prohormone processing and regulated secretion. Furthermore, we demonstrate for the first time that SN is capable of stimulating LH secretion from ex vivo mouse pituitaries, an effect previously documented only in non-mammalian vertebrate species and LβT2 cells. Exogenous SN stimulation significantly increased LH release from adult male (1.4x; p<0.01) and proestrous female (2.4x; p<0.0001) murine pituitaries. Notably, we found that SN treatment had no observed effect on LH secretion in prepubertal (PND14) male and female pituitaries, indicating that SN may function primarily in mature gonadotropes to promote fertility and estrous cycle progression.