Gastrointestinal Tract Disorder in Natriuretic Peptide Receptor B Gene Mutant Mice

Abstract

Natriuretic peptide receptor B (NPR-B), which has high affinity for C-type natriuretic peptide (CNP) and synthesizes intracellular cGMP, may be involved in gastrointestinal tract (GIT) regulation. A mutant allele of the NPR-B-encoding gene (Npr2) is responsible for the phenotype of the short-limb dwarfism (SLW) mouse. Homozygosity for this autosomal-recessive gene (slw/slw) leads to dwarfism and death before weaning because of milk retention in the stomach and intestinal distention. To elucidate the relationship between CNP/NPR-B signaling and GIT function, we investigated the association between Npr2 mutation and the GIT phenotype in slw/slw mice. The pylorus and large intestine of the mutants did not respond to CNP stimulation; further, they showed pyloric lumen narrowing with randomly aligned circular muscle cells. Comparison of the cGMP and neuronal marker distribution in GIT tissues confirmed cGMP expression in neuronal tissues. An Auerbach's plexus and submucosal tissues of the mutants didn't express cGMP and expressed Ca(2+). In contrast, those of normal mice (controls) expressed both cGMP and Ca(2+). Sequencing revealed that the causative Npr2 mutation was a 7-base deletion in exon 8, resulting in a frameshift and premature termination codon appearance. Therefore, the GIT phenotype of slw/slw mice is because of a CNP/NPR-B-signaling defect caused by an Npr2 mutation. These results facilitate better understanding of the role of CNP/NPR-B signaling in GIT motility.

Electroacupuncture promotes the gastrointestinal motility of diabetic mice by CNP/NPR‐B‐cGMP and PDE3A‐cGMP signaling

“…When CNP binds to NPR-B, it could activate GC to catalyze the transformation of cGMP from GTP and then cause a relaxation of the gastric and colonic smooth muscles. [17][18][19] There was a report which confirmed that inhibitory effect of CNP on gastric smooth muscle was strengthened in diabetic rat via up-regulation of cGMP, 20 are the most common isoforms in GI tract, and PDE3 is a main regulator of murine gastrointestinal circular muscle contraction, while higher concentration of PDE2 could partly influence the gut motility. 22,23 Cai et al 24 confirmed only the expression level of PDE3 was decreased in gastric smooth muscle of diabetic rats.…”

“…As a crucial peptide hormone of the natriuretic peptide family, CNP could be secreted in GI tissue and preferentially binds to its specific receptor NPR‐B, which was distributed in the GI smooth muscle layer. When CNP binds to NPR‐B, it could activate GC to catalyze the transformation of cGMP from GTP and then cause a relaxation of the gastric and colonic smooth muscles . There was a report which confirmed that inhibitory effect of CNP on gastric smooth muscle was strengthened in diabetic rat via up‐regulation of cGMP, but the effect of CNP on colon in the diabetic model has not been explored.…”

Roles of EDNs in regulating oviductal NO synthesis and smooth muscle motility in cows

“…Isometric contraction test of oviductal smooth muscle was performed as described previously (Sogawa et al 2010, Ning et al 2014) with some modifications. Briefly, the ampullary (n = 5) and isthmic (n = 6) tissues of bovine oviducts obtained from cows after ovulation were cut open and 3-mm-length strips were prepared.…”

Transmembrane guanylate cyclase in intestinal pathophysiology

“…Expression and/or activity of GC-A, GC-B, and their ligands can be found in the intestinal tract of rabbits, rodents, and humans in a wide variety of cell types including IECs, smooth muscle, myenteric and submucosal neurons, myofibroblasts and the interstitial cells of Cajal (ICC) [2 , [42][43][44][45]. ANP/GC-A is a classical regulator of sodium flux in the intestine and has recently been shown to regulate CFTR expression in IECs [43].…”

“…CNP/GC-B regulates circular smooth muscle relaxation and may act directly in the ICC to control small bowel pacemaker currents [44,45]. Notably, although genetic deletion of GC-B in mice does not result in a severe gastrointestinal phenotype, two separately reported GC-B truncation mutants result in a lethal loss of intestinal motility [42,46,47]. Best described is the short-limb dwarfism (slw) mouse which lacks the intracellular domain of GC-B.…”