Neuronostatin, a Novel Peptide Encoded by Somatostatin Gene, Regulates Cardiac Contractile Function and Cardiomyocyte Survival

Abstract

Background: Neuronostatin peptide is a somatostatin gene derivative, whose functions are largely unknown. Results: Neuronostatin activates p38 MAPK and JNK attenuating endothelin-1-induced cardiac contractility and compromising cardiomyocyte viability. Conclusion: Neuronostatin has multiple biological effects in cardiomyocytes. Significance: Receptors for neuronostatin need to be identified to further characterize the functions of the peptide.

Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107

“…Whether GPR107 is the initial receptor for neuronostatin in this model or is a receptor expressed in downstream neuronal circuits activated by neuronostatin cannot be determined by these studies; however, a combination of the in vitro and the in vivo results point promisingly to the identification of GPR107 as the cognate receptor for this recently discovered peptide hormone. This experimental approach can now be employed to study the potential physiological relevance of the additional actions of neuronostatin in brain (20), heart (10,19), and pancreas (15), studies that were not possible prior to identification of the potential neuronostatin receptor.…”

“…Neuronostatin activates KATOIII cells (15), cardiomyoctes (10,19), hypothalamic neurons (15), and pancreatic ␣-cells (15). Therefore, we screened these cell types for the candidate orphan GPCRs using PCR (Fig.…”

“…This elevation in MAP was found to be dependent upon two separate mechanisms: activation of the sympathetic nervous system and stimulation of vasopressin secretion from the posterior pituitary gland, since the first phase was blocked by pretreatment with phentolamine, while the second phase was reversed by pretreatment with a vasopressin receptor antagonist (20). In addition, neuronostatin directly altered the contractility of isolated cardiomyocytes and whole heart preparations via PKA and/or JNK-dependent mechanisms (10,19). Because neuronostatin is derived from the somatostatin preprohormone, any attempt to compromise the production of neuronostatin would result in loss of somatostatin as well.…”

“…Neuronostatin directly initiates specific signaling cascades in at least four different cell types: hypothalamic neurons (15), cardiomyocytes (10,19), pancreatic ␣-cells (15), and a gastric tumor cell line, KATOIII (15). We reasoned that because these cell types responded to direct application of neuronostatin in vitro, they must express a neuronostatin receptor(s).…”

Neuronostatin Attenuates Myocardial Contractile Function through Inhibition of Sarcoplasmic Reticulum Ca2+-ATPase in Murine Heart

“…More recent evidence from our group suggested that neuronostatin inhibits cardiac contractile function via a protein kinase A (PKA)- and c-Jun N-terminal kinase (JNK)-dependent mechanism [8]. In addition, neuronostatin attenuates endothelin-1 (ET-1)-induced left ventricular contractility in isolated rat hearts via p38 MAPK and JNK phosphorylation-dependent mechanisms [9]. …”