C-type natriuretic peptide enhances amylase release through NPR-C receptors in the exocrine pancreas

Abstract

Several studies show that C-type natriuretic peptide (CNP) has a modulatory role in the digestive system. CNP administration reduces both jejunal fluid and bile secretion in the rat. In the present study we evaluated the effect of CNP on amylase release in isolated pancreatic acini as well as the receptors and intracellular pathways involved. Results showed that all natriuretic peptide receptors were expressed not only in the whole pancreas but also in isolated pancreatic acini. CNP stimulated amylase secretion with a concentration-dependent biphasic response; maximum release was observed at 1 pM CNP, whereas higher concentrations gradually attenuated it. The response was mimicked by a selective natriuretic peptide receptor (NPR-C) agonist and inhibited by pertussis toxin, strongly supporting NPR-C receptor activation. CNP-evoked amylase release was abolished by U-73122 (PLC inhibitor) and 2-aminoethoxydiphenyl borate (2-APB) [an inositol 1,4,5-triphosphate (IP(3)) receptor antagonist], partially inhibited by GF-109203X (PKC inhibitor), and unaltered by ryanodine or protein kinase A (PKA) and protein kinase G (PKG) inhibitors. Phosphoinositide hydrolysis was enhanced by CNP at all concentrations and abolished by U-73122. At 1 and 10 pM, CNP did not affect cAMP or guanosine 3',5'-cyclic monophosphate (cGMP) levels, but at higher concentrations it increased cGMP and diminished cAMP content. Present findings show that CNP stimulated amylase release through the activation of NPR-C receptors coupled to the PLC pathway and downstream effectors involved in exocytosis. The attenuation of amylase release was likely related to cAMP reduction. The augmentation in cGMP supports activation of NPR-A/NPR-B receptors probably involved in calcium influx. Present findings give evidence that CNP is a potential direct regulator of pancreatic function.

The C-Type Natriuretic Peptide Induces Thermal Hyperalgesia through a Noncanonical Gβγ-dependent Modulation of TRPV1 Channel

“…Immunoprecipitation of NPR-C, but not NPR-B, specifically co-precipitated the Gα i , but not Gα q or Gα s subunits in mouse DRG neurons (Figure 3B). Activation of a number of Gα i -coupled GPCRs, including NPR-C, has been shown to activate PKC via the dissociation of Gβγ subunits from Gα i upon receptor activation, and subsequent activation of PLCβ (Murthy and Makhlouf, 1999; Murthy et al, 2000; Shi et al, 2003; Anand-Srivastava, 2005; Chen et al, 2005; Pandey, 2005a; Sabbatini et al, 2007). Activation of Gα i/o -coupled GPCRs also leads to the activation of MAPK/ERK and PLCβ-DAG-PKC signaling cascades.…”

PKD3 Is the Predominant Protein Kinase D Isoform in Mouse Exocrine Pancreas and Promotes Hormone-induced Amylase Secretion

“…Acinar Cell Secretion Assays-CCK-stimulated secretions were collected and assayed as described previously (38). Briefly, infected and control acini were washed and resuspended in Krebs-Henseleit buffer (KHB) (142 mM NaCl, 23.8 mM NaHCO 3 , 4.83 mM KCl, 0.96 mM KH 2 PO 4 , 1.20 mM MgSO 4 , 12.5 mM HEPES, 5 mM glucose, and 2.2 mM CaCl 2 , pH 7.4).…”

Atrial natriuretic peptide reduces inflammation and enhances apoptosis in rat acute pancreatitis

“…8,9 We previously reported that ANP through the natriuretic peptide type C receptor (NPR-C) coupled to the phospholipase C/protein kinase C (PLC/PKC) pathway stimulates pancreatic secretion, and negatively regulates cAMP intracellular levels in the pancreas evoked by pancreatic secretagogues like secretin and vasoactive intestinal peptide. [10][11][12] ANP stimulates cAMP efflux of the acinar cell through multidrug resistance-associated protein type 4 (MRP4) as a regulatory mechanism in addition to phosphodiesterase activity to restrict the intracellular accumulation of the cyclic nucleotide within the acinar cell to prevent cell damage. 13 In this sense, we reported that early AP is aggravated by enhanced intracellular cAMP, but pre-treatment with ANP through NPR-C activation attenuates the severity of the disease by extruding the second messenger.…”