Neuronostatin exerts actions on pituitary that are unique from its sibling peptide somatostatin

Neuronostatin, a somatostatin gene-encoded peptide, exerts important physiological and metabolic actions in diverse tissues. However, the direct biological effects of neuronostatin on pituitary function of humans and primates are still unknown. This study used baboon (Papio anubis) primary pituitary cell cultures, a species that closely models human physiology, to demonstrate that neuronostatin inhibits basal, but not ghrelin-/GnRH-stimulated, growth hormone (GH) and luteinizing hormone (LH) secretion in a dose- and time-dependent fashion, without affecting the secretion of other pituitary hormones (prolactin, ACTH, FSH, thyroid-stimulating hormone (TSH)) or changing mRNA levels. Actions of neuronostatin differs from somatostatin which in this study reduced GH/PRL/ACTH/LH/TSH secretion and GH/PRL/POMC/LH gene expression. Remarkably, we found that inhibitory actions of neuronostatin are likely mediated through: (1) the orphan receptor GPCR107 (found to be highly expressed in pituitary compared to somatostatin-receptors), (2) common (i.e. adenylyl cyclase/protein kinase A/MAPK/extra-/intracellular Ca²⁺ mobilization, but not phospholipase C/protein kinase C/mTOR) and distinct (i.e. PI3K) signaling pathways than somatostatin and; (3) dissimilar molecular mechanisms than somatostatin (i.e. upregulation of GPCR107 and downregulation of GHS-R/Kiss1-R expression by neuronostatin and, upregulation of sst1-5 expression by somatostatin). Altogether, the results of this study provide the first evidence that there is a functional neuronostatin signaling circuit, unique from somatostatin, which may work in concert with somatostatin to fine-tune hormone release from somatostropes and gonadotropes.