Uroguanylin (human)

Discovery

UGN was first isolated from opossum urine in 1993 and was identified in humans in 1994. In nonmammals, ugn was first cloned from the eel in 2001. Also, in other vertebrates, ugn has been found. An ugn-like sequence is observed in the nucleotide database of an invertebrate, Ciona intestinalis. lgn was first cloned from the opossum in 1999.

Structure

UGN consists of 15–17 aa residues that are released from the C-terminus of proUGN. The fourth and 12th Cys and the seventh and 15th Cys form a disulfide bond, respectively, and the two rings give rise to the formation of two stereoisomers, of which only one is active. Some UGNs have a C-terminal extension , which may contribute to stabilizing the active isomer. The ninth aa residue is nonaromatic and thus resistant to chymotrypsin-like proteases in the renal tubule. These features are shared among all UGNs found. Lgn possesses a nonaromatic aa residue at the same position, but lacks the 15th Cys residue, resulting in the lack of the second disulfide ring. Most of the 15–17 aa residues are conserved across vertebrate species, though some are different, especially in Lgn. In some species, 1–2 extra aa residues are present at the C-terminus. The prosegment is variable except for the conserved Leu/Lys-rich region located in the upstream of proUGN.

Properties

Mr and pI of human UGN are 1667.9 and 3.19, respectively. UGN is soluble in water, alcohol, and watercontaining organic solvent. UGN in solution is stable at neutral pH. UGN in water is stable at -20°C for more than 1 year. Solubilization and storage methods of Lgn may be similar to those of UGN.

Gene, mRNA, and precursor

In humans, UGN consisting of three exons is located on chromosome 1 (1p34.2) with GN. Similar colocalization on a chromosome is observed in other vertebrate species. The translated preproUGN of 112 aa residues contains the signal peptide and the mature peptide. ProUGN is released from cells and processed into UGN during circulation or on the intestinal and renal tubular lumen. The mature region is well or moderately conserved among vertebrate UGNs or in opossum Lgn, respectively , although the precise processing mechanism needs to be investigated in nonmammalian Ugns. A splice variant is suggested in the European eel.

Receptors

GUCY2C, a membrane protein consisting of an extracellular ligand-binding domain, a membrane-spanning domain, a kinase-like domain, and a cyclase catalytic domain, is the primary receptor for both UGN and GN .A shorter GUCY2C, a splice variant, is expressed in some colorectal cancer cells. In contrast to one GUCY2C in mammals, at least two gucy2c exist in teleost fish. In eels, at the cGMP production, Gucy2c1 is stimulated primarily by Ugn while Gucy2c2 responds to Ugn less effectively than Gn  Structure of human preproUGN (A) and UGN (B), and comparison of vertebrate UGN and opossum Lgn (C). (B) The schematic view is based on previous reports. (C) Arrowheads indicate the ninth aa residue characteristic to UGN. 350 32B.  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. The presence of additional UGN receptor(s) has been predicted. In the opossum, Gucy2c is also a receptor for Lgn.

Agonists

Sts produced by enterotoxigenic E. coli are exogenous ligands of GUCY2C. Sts exert stronger effects for GUCY2C than UGN 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.

Clinical implications

There is no known disease related to UGN. A function for the intestinal fluid secretion has led scientists to apply UGN for anticonstipation. The facts of decreased UGN mRNA expression in some colorectal cancers and promoted epithelial proliferation in the loss of UGN suggest a clinical application of UGN to prevent the enlargement of colorectal tumors. The evidence of decreased UGN in obesity and the implication of UGN as an enterocerebral natriuretic factor could also be keys for UGN-utilizing improvement of obesity.

General Description

Uroguanylin is a peptide hormone consisting of 15–17 aa residues that binds to the guanylyl cyclase C (GUCY2C) receptor to produce cGMP, which is often more effective than guanylin (GN). It plays important roles in regulating ion and water transport and maintaining epithelial homeostasis in the intestine and kidney. Opossum lymphoguanylin (Lgn) is more similar to UGN than to GN, and thus, is described here.

Clinical Use

Two UGN/GN agonists, linaclotide and plecanatide, have recently been approved in the United States, European Union, Japan, and other countries for treatment of irritable bowel syndrome and chronic constipation. They have also been approved in the United States for treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation, respectively.