Neuronostatin-19: brain and gut peptide fragment (human/canine/porcine)

What this is

Neuronostatin is a small peptide hormone that the body produces from the same gene as somatostatin — the gene makes one long protein that is cleaved into both peptides. It was discovered by bioinformatic prediction in 2008 and is found in the brain, pancreas, heart, stomach, and other tissues where somatostatin is also made (Samson 2008, J Biol Chem). The canonical active form purified from pig tissue is a 13-residue C-terminally amidated peptide; the sequence stored on this card (APSDPRLRQFLQKSLAAAA, 19 residues) is a longer N-terminal fragment of the preprosomatostatin precursor that overlaps the same region and has been detected in mammalian neuropeptidome surveys (Petruzziello 2012, J Proteome Res). Researchers care about neuronostatin because it is encoded by a famously well-studied gene, yet it appears to act on a completely different receptor pathway from somatostatin itself.

History

Neuronostatin was identified in 2008 by William Samson's group through evolutionary-conservation analysis of the preprosomatostatin sequence: they noticed a conserved stretch outside the somatostatin-14 / somatostatin-28 region that had the hallmarks of a separately cleaved peptide hormone. They confirmed the prediction by immuno-affinity purification of an amidated 13-residue peptide from porcine tissue and showed it was co-produced with somatostatin in pancreas, hypothalamus, heart, stomach, cerebrum, and spleen (Samson 2008, J Biol Chem). Subsequent work confirmed co-localization with somatostatin in the rat hypothalamic periventricular nucleus and demonstrated direct effects on cultured neurons (Dun 2010, Neuroscience). The orphan G-protein-coupled receptor GPR107 was nominated as a candidate receptor in 2012 (Yosten 2012, Am J Physiol Regul Integr Comp Physiol) and later supported by α-cell signaling experiments (Elrick 2016, Am J Physiol Regul Integr Comp Physiol).

What it does

In published animal and cell studies neuronostatin acts across several systems where somatostatin is also expressed, but with effects that are distinct from somatostatin's:

• In the brain, it depolarizes paraventricular hypothalamic neurons and induces c-Fos expression in hippocampus, cerebellum, anterior pituitary, and gastrointestinal tissues after systemic administration in rodents (Samson 2008, J Biol Chem). In cultured rat hypothalamic neurons it mobilizes intracellular calcium and produces a mix of depolarizing and hyperpolarizing responses, indicating it engages more than one downstream pathway (Dun 2010, Neuroscience).
• In the pancreas, it increases proglucagon mRNA in α-cells and promotes glucagon release under low-glucose conditions, working through PKA phosphorylation in a way that does not require a rise in cAMP (Elrick 2016, Am J Physiol Regul Integr Comp Physiol).
• In the heart, intravenous infusion in mice inhibits cardiac contractile function through a mechanism dependent on PKA and JNK signaling (Hua 2009, Am J Physiol Regul Integr Comp Physiol), and in cardiomyocyte preparations it activates p38 MAPK and JNK, attenuates the positive inotropic response to endothelin-1, and reduces cell viability (Vainio 2012, J Biol Chem).

Importantly, neuronostatin does not activate the somatostatin receptors (SSTR1–SSTR5) (Samson 2008, J Biol Chem) — so despite sharing a parent gene with somatostatin, its biology runs on a separate receptor.

Mechanism

The receptor for neuronostatin has been studied most directly as the orphan class-IV GPCR GPR107. RNA-interference knockdown of GPR107 in pancreatic α-cells abolishes neuronostatin-induced PKA phosphorylation and proglucagon mRNA accumulation, and GPR107 colocalizes with neuronostatin on mouse and human α-cells (Yosten 2012, Am J Physiol Regul Integr Comp Physiol; Elrick 2016, Am J Physiol Regul Integr Comp Physiol). The α-cell pathway is notable because PKA is activated without a measurable rise in cAMP, consistent with a non-canonical Gs-independent route.

The canonical bioactive form purified from porcine tissue is C-terminally amidated; that amidation is a post-translational modification not captured by the 19-letter sequence stored on this card, which represents an N-terminal fragment of the preprosomatostatin precursor that includes the neuronostatin region (Samson 2008, J Biol Chem; Petruzziello 2012, J Proteome Res). Synthetic neuronostatin peptides used in the published studies above include the C-terminal amide.

In cardiomyocytes and whole heart preparations the downstream signaling involves PKA, p38 MAPK, and JNK rather than the receptor-distal pathway described in α-cells, and the functional consequence is suppression of contractility and antagonism of β-adrenergic and endothelin-1 inotropic responses (Hua 2009, Am J Physiol Regul Integr Comp Physiol; Vainio 2012, J Biol Chem).

Evidence

• Human: No published human clinical studies. Human neuronostatin sequence is reported in the discovery paper and the peptide has been detected in mammalian neuropeptidome surveys (Samson 2008, J Biol Chem; Petruzziello 2012, J Proteome Res).
• Animal: Rodent studies have shown CNS effects (c-Fos induction in multiple brain regions; depolarization of hypothalamic neurons), pancreatic effects on α-cell glucagon biology, and cardiac effects (inhibition of contractility) (Samson 2008; Dun 2010; Hua 2009; Vainio 2012).
• In vitro: Cultured rat hypothalamic neurons mobilize calcium in response to neuronostatin (Dun 2010, Neuroscience); isolated cardiomyocytes show activation of PKA/p38/JNK and reduced viability (Vainio 2012, J Biol Chem); pancreatic α-cell lines show GPR107-dependent PKA phosphorylation and proglucagon induction (Elrick 2016, Am J Physiol Regul Integr Comp Physiol).

Known effects

• CNS activation (rodent) — Depolarization of paraventricular hypothalamic neurons and broad c-Fos induction across hippocampus, cerebellum, anterior pituitary, and gut (Samson 2008).
• Pancreatic α-cell signaling (rodent / cell line) — Increased proglucagon mRNA and glucagon release in low glucose, via GPR107 and cAMP-independent PKA (Elrick 2016).
• Cardiac suppression (mouse, ex vivo / in vivo) — Reduced contractility and antagonism of endothelin-1-induced positive inotropy, with PKA, p38 MAPK, and JNK involvement (Hua 2009; Vainio 2012).
• Receptor specificity — Does not activate somatostatin receptors SSTR1–SSTR5 (Samson 2008).

Regulatory status

Neuronostatin is an endogenous peptide and a research reagent. It is not an approved drug, has no marketing authorization in the US or EU, and is not currently the subject of an FDA or EMA review. Synthetic neuronostatin is used in academic laboratories to study GPR107 signaling and the cardiovascular, neuroendocrine, and metabolic effects of the somatostatin-gene-derived peptide system.

Related peptides

• Somatostatin — encoded by the same gene; the prototypical product of preprosomatostatin processing, but signals through the SSTR1–SSTR5 receptor family that neuronostatin does not activate.
• Cortistatin — another preprosomatostatin-family peptide with overlapping but distinct receptor pharmacology from somatostatin.

Open questions

• Whether GPR107 is the sole receptor for neuronostatin, or whether additional receptors mediate the brain and cardiac effects, has not been resolved in the published literature.
• The exact processing pathway from preprosomatostatin to the mature amidated 13-residue peptide, and the role (if any) of longer fragments such as the 19-residue stored sequence, remain incompletely characterized.
• No human pharmacology or safety data have been published.