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Questions And Answer

• Discovery

  GN was first isolated from the rat jejunum and its gene was identified in humans in 1992. In nonmammalian vertebrates, gn and rgn were first cloned from the Japanese eel in 2003. Except for avians, gn has also been found in other vertebrates.;

• Structure

  GN consists of 15 aa residues that are cleaved from the C-terminus of proGN . The fourth and 12th Cys and the seventh and 15th Cys form a disulfide bond, respectively. The two rings give rise to the formation of two stereoisomers, of which only one is active. The aromatic aa residue (Tyr/Phe) at the ninth position is targeted by chymotrypsin-like proteases in the renal tubule. These features are shared among all GNs found as well as eel Rgn. Most of the 15 aa residues are conserved across vertebrate species, whereas an extra Leu residue is present in eel Rgn. The prosegment is variable with the exception of a conserved Leu/Lys-rich region located in the upstream of proGN.
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• Properties

  The Mr and pI of human GN are 1458.7 and 4.56, respectively. GN is soluble in water, alcohol, and water-containing organic solvents. GN is stable at neutral pH, but at acidic pH, it is more easily converted to the inactive stereoisomer. GN in water is stable at -20°C for more than 1 year. Empirically, eel Rgn has been solubilized and stored like GN.;

• Gene, mRNA, and precursor

  GN is located near UGN on chromosome 1 in humans (1p34.2). Similar colocalization on a chromosome is found in other vertebrate genome databases. Three exons divided by two introns are transcribed and translated into preproGN of 115 aa residues containing the signal peptide and the mature peptide. ProGN is released from cells and processed into GN during circulation or on the intestinal and renal tubular lumen. The mature region is conserved among vertebrate GNs and eel Rgn , although the precise processing mechanism needs to be studied in nonmammalian Gns and Rgn. No significant splice variant is known at present.;

• Regulation of synthesis

  GN promoter sequence in the 50 -flanking region lacks typical TATA and CAAT boxes, but possesses a putative TATA-alternative motif, “TTTAAAA,” and several potential binding/responsive sites for transcription factors/elements such as AP-1, AP-2, SP1, GRE, GCF, and HNF-1 in humans and mice. HNF-1 could play a role in restricting GN expression to the intestine. In rodent and eel intestines, GN is synthesized in goblet cells. In eels, rgn could be produced in the kidney as significanly as in the intestine.;

• Receptors

  GUCY2C, a membrane protein consisting of an extracellular ligand-binding domain, a membrane-spanning domain, a kinase-like domain, and a catalytic guanylyl cyclase (GC) domain, is the primary receptor for both GN and UGN . A shorter GUCY2C, a splice variant, is expressed in some colorectal cancer cells. In contrast to the one GUCY2C in mammals, at least two isoforms of gucy2c exist in teleost fish. At the cGMP production in COS cells expressing each eel isoform, the potency rankings of Gucy2c2 and Gucy2c1 are Gn ≥ Rgn > Ugn and Rgn ≤ Gn < Ugn, respectively. At least one gucy2c sequence has been found in other vertebrates. Furthermore, another type of GC receptor, GUCY2D, expressing in the murine olfactory epithelia, is reported to be stimulated by GN and UGN, while the presence of additional GN receptor(s) has been predicted.;

• Agonists

  Sts produced by enterotoxigenic E. coli are exogenous ligands of GUCY2C. Sts exert stronger effects for GUCY2C than GN in mammals and substantial effects for one medaka Gucy2c (Olgc9), but not for other fish cloned Gucy2cs. Other major agonists are synthetic peptides modified from GN/UGN, linaclotide and plecanatide.;

• Biological functions

  The primary site of GN action is the intestine where GUCY2C expression is most plentiful. The kidney, liver, gall bladder, bile duct, testis, trachea, salivary glands, and nasal mucosa are also possible target sites. In eels and medaka, the major sites of gucy2c1 and gucy2c2 expression are the intestine and kidney. In the intestine, GN is produced in goblet cells and secreted into the lumen. GN binding to the apically located GUCY2C induces Cl^- and HCO3^- secretion via CFTR and some SLC26 members and inhibits Na+ absorption via NHE3, which eventually drives intestinal water secretion.
  GN-GUCY2C signaling suppresses intestinal tumorigenesis. In the intestine, GN is more active at pH 8.0 than at pH 5.0. Circulating and locally produced GN also acts on the renal tubule to induce natriuresis, kariuresis, and diuresis, presumably by affecting the NHE3 and K+ channel(s). However, this GN’s effects could be limited due to the degradation of GN by proteases on the brush border of the renal tubule. In eels, on the other hand, Gn and Rgn affect Cftr in the intestine, but it is notable that Gn and Rgn inhibit Nkcc2 for decreased NaCl absorption and may induce some Slc26 members for HCO3 - secretion under a seawater environment, probably for osmoregulation. In these described actions, GN is often less effective than UGN in mammals while Gn is more effective than Rgn and Ugn in eels. Concerning eel Rgn, its mRNA expression in the intestine and kidney slightly or hardly change after seawater transfer of the fish, suggesting that Rgn may have roles different from those of Gn and Ugn. In a heterologous system, eel Rgn inhibits NHE3 as does rat UGN, but is less effective than rat UGN in the rat perfused renal tubule. In addition, the olfactory GN-GUCY2D signaling in mice suggests more GN functions.;

• Clinical implications

  There is no known disease related to GN. A function for intestinal fluid secretion has led scientists to apply GN for anticonstipation. Decreased GN mRNA expression in some colorectal cancers, promoted epithelial proliferation in the loss of GN, and decreased GN in obesity suggest a clinical application of GN to prevent the enlargement of colorectal tumors and improve obesity.;

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