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

in Journal of Endocrinology
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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.

 

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    Direct effect of neuronostatin (NST) on baboon pituitary hormone secretion. Dose response (4 h) of NST (dose between 10−7 M and 10−11 M; white columns) on the secretion of baboon GH, PRL, ACTH, FSH, LH and FSH. Data are expressed as percent of control (set at 100%; black columns) and represent the mean ± s.e.m. (n = 4 individual experiments, 3–4 wells/experiment). Values that do not share a common letter (a, b, c) are statistically different.

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    Time-dependent effect of neuronostatin (NST; 10−7 M; 30 min, 4, 12, and 24 h; white columns) on the secretion of baboon GH, PRL, ACTH, FSH, LH and FSH. Data are expressed as percent of control (set at 100% at 30 min of incubation; black columns) and represent the mean ± s.e.m. (n = 4 individual experiments, 3–4 wells/experiment). Values that do not share a common letter (a, b and c) are statistically different in the vehicle-treated controls at different times. Asterisks indicate values of the NST-treated groups at different times of incubation that significantly differ from their respective vehicle-treated control values (*P < 0.05).

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    Comparison between direct effect of 4-h and 24-h treatment of neuronostatin (NST; 10−7 M; white columns) and somatostatin (SST; 10−7 M; grey columns) on the secretion of baboon GH, PRL, ACTH, FSH, LH and FSH (A) and, on the expression of GH, PRL, POMC, FSH, LH, FSH and pituitary transcription factor-1 (Pit-1) (B) in primary pituitary cell cultures from baboons. Values are expressed as percentage of controls (4 h or 24 h, set at 100% within each experiment; black columns), and represent the mean ± s.e.m. of four independent experiments (three to four wells/experiment). Values that do not share a common letter (a, b, c, d) differ significantly (P < 0.05).

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    Interaction of neuronostatin (NST; 10−7 M) and/or somatostatin (SST; 10−7 M) and the main stimulatory regulator of somatotrope and gonadotrope function (ghrelin and gonadotrophin-releasing hormone (GnRH), respectively) in primary pituitary cell cultures from baboons. Effect of 4-h treatment of NST or SST and/or ghrelin (10 nM) on GH secretion and, of NST or SST and/or GnRH (10 nM) on LH secretion. Values are expressed as percentage of controls, set at 100% within each experiment, and represent the mean ± s.e.m. of three independent experiments (three to four wells/experiment). Values that do not share a common letter (a, b, c, d) differ significantly (P < 0.05).

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    Intracellular signaling pathways of neuronostatin (NST)- and somatostatin (SST)-inhibited baboon GH and LH secretion. Effect of the inhibition of AC (MDL-12330A; 10 μM), protein kinase A (H89; 15 μM), PLC (U73122; 50 μM), protein kinase C (Go6983; 20 μM), extracellular Ca2+ L-type channels (nifedipine; 1 μM), intracellular Ca2+ channels (thapsigargin; 10 μM), MAPK (PD-98059; 10 μM), mTOR (rapamycin; 10 nM) and PI3K (wortmannin; 1 μM) on NST- and SST-inhibited GH (A) and LH (B) secretion. On the day of the experiment, inhibitors were added to the incubation media 90 min before NST or SST treatment (4 h; 10−7 M). Values are expressed as percentage of vehicle-treated controls without inhibitor (set at 100%) within each experiment, and represent the mean ± s.e.m. of four independent experiments (three to four wells/treatment per experiment). Values that do not share a common letter (a, b, c) significantly differ (P < 0.05).

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    Presence and regulation of the expression of key pituitary receptors for the regulation of somatotrope and gonadotrope function. (A) Presence of GPCR107 (absolute mRNA copy numbers) in the pituitary (PIT; white column) and hypothalamus (HPT; black column) of baboons, as determined by quantitative rtRT-PCR. (B) Effects of neuronostatin (NST; 10−7 M; white columns) and somatostatin (SST; 10−7 M; grey columns) treatment on the expression of pituitary receptors for SST (sst1–sst5), NST (GPCR107), GHRH (GHRH-R), ghrelin (GHS-R) and Kiss1 (Kiss1-R) in primary pituitary cell cultures from baboons after 4 h of treatment. Data are expressed as absolute mRNA copy numbers per 0.05 μg total RNA in the whole pituitary of female baboons ((A); n = 5), or as percentage of vehicle-treated controls ((B); set at 100%; black columns) in primary pituitary cell cultures from baboons and represent the mean ± s.e.m. (n = 4 individual experiments; 3–4 wells/experiment). Asterisks indicate values that significantly differ from their respective control values (**P ≤ 0.01).

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