| Identification | Back Directory | [Name]
GUANYLIN (RAT) | [CAS]
144940-98-7 | [Synonyms]
GUCA2
GUCA2A
GUANYLIN
Cys7-Cys15)
GUANYLIN (RAT)
GUANYLIN (RAT, MOUSE)
PNTCEICAYAACTGC(Disulfide bridge：Cys4-Cys12
ADLCEICAFAACTGCL(Disulfide bridge：Cys4-Cys12
ANTI-GUCA2A (CENTER) antibody produced in rabbit
PRO-ASN-THR-CYS-GLU-ILE-CYS-ALA-TYR-ALA-ALA-CYS-THR-GLY-CYS
PRO-ASN-THR-CYS-GUE-ILE-CYS-ALA-TYR-ALA-ALA-CYS-THR-GLY-CYS
PNTCEICAYAACTGC(DisulfidebondsbetweenCys4-Cys12andCys7-Cys15)
H-PRO-ASN-THR-CYS-GLU-ILE-CYS-ALA-TYR-ALA-ALA-CYS-THR-GLY-CYS-OH
H-Pro-Asn-Thr-Cys-Glu-Ile-Cys-Ala-Tyr-Ala-Ala-Cys-Thr-Gly-Cys-OH(Cys4-Cys12, Cys7-Cys15)
PRO-ASN-THR-CYS-GLU-ILE-CYS-ALA-TYR-ALA-ALA-CYS-THR- GLY-CYS(DISULFIDE BRIDGE: CYS4-CYS12, CYS7-CYS15) | [Molecular Formula]
C60H90N16O22S4 | [MDL Number]
MFCD00187932 | [MOL File]
144940-98-7.mol | [Molecular Weight]
1515.71 |
| Questions And Answer | Back Directory | [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.
 | [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. |
| Hazard Information | Back Directory | [Description]
Guanylin is a peptide hormone consisting of 15 aa residues that
binds to the guanylyl cyclase C (GUCY2C) receptor to produce cGMP. It plays an important role in regulating ion and
water transport and maintaining epithelial homeostasis in the
intestine and kidney. Eel renoguanylin (Rgn) is more similar
to GN than to uroguanylin (UGN), and thus is described
here. | [Uses]
Guanylin (rat, mouse) is an endogenous intestinal guanylyl cyclase activator. | [Clinical Use]
Two GN/UGN agonists, linaclotide and plecanatide,
have recently been approved in the United States, European Union, Japan, and other countries to treat irritable
bowel syndrome and chronic constipation. They have
also been approved in the United States to treat chronic
idiopathic constipation and irritable bowel syndrome
with constipation, respectively. |
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