Alternative titles; symbols
HGNC Approved Gene Symbol: GUCA2B
Cytogenetic location: 1p34.2 Genomic coordinates (GRCh38) : 1:42,153,410-42,155,820 (from NCBI)
Uroguanylin and guanylin (GUCA2A; 139392), peptide homologs of the bacterial heat-stable enterotoxins (e.g., the E. coli ST toxin; STa), are endogenous activators of the guanylate cyclase-2C receptor (GUCY2C; 601330), which synthesizes cyclic GMP (cGMP), a key component of several intracellular signal transduction pathways.
Peptide Isolation
Kita et al. (1994) searched for members of the guanylin-like family and purified a 16-amino acid peptide, which they termed uroguanylin, from human urine. The uroguanylin peptide shares amino acid sequence homology with guanylin. By systematic isolation of circulating regulatory peptides that generate cGMP as second messengers, Hess et al. (1995) identified a 24-amino acid peptide with a molecular mass of 2.6 kD, which they termed guanylate cyclase C activating peptide II (GCAP II), and identified as the 'circulating form of uroguanylin.' The 16 C-terminal amino acids are identical to uroguanylin, and 8 of 13 C-terminal residues are conserved between GCAP II, uroguanylin, and E. coli STa. By immunohistochemistry, Hess et al. (1995) showed that GCAP II localized to enteroendocrine cells of colonic mucosa.
Gene Isolation
Using human uroguanylin cDNA as a probe to screen a human genomic library, Miyazato et al. (1997) isolated the gene for uroguanylin and determined the full-length sequence, which encodes a deduced 112-amino acid protein. The entire nucleotide sequence that corresponds to the 16 amino acid residues of mature uroguanylin is included in the third exon. The GUCA2B gene also has multiple binding sites for the promoter-specific transcription factors AP1 (165160) and AP2 (107580), and a cAMP-regulated enhancer element. RNA blot analysis showed that the human uroguanylin mRNA is expressed in the gastric fundus and pylorus, as well as in the intestine.
Whitaker et al. (1997) cloned the mouse Guca2b gene (which the authors referred to as Guca1b). In the mouse, uroguanylin mRNA is most prominent in the proximal small intestine, whereas guanylin mRNA is predominantly expressed in distal small intestine and colon. The upstream promoter sequence of the mouse uroguanylin gene contains consensus binding sites for several known transcription factors, including HNF1 (142410) and Sp1 (189906).
Miyazato et al. (1997) determined that the human GUCA2B gene contains 3 exons.
Whitaker et al. (1997) found that the mouse uroguanylin and guanylin genes are structurally similar, both being composed of 3 short exons.
By fluorescence in situ hybridization, Miyazato et al. (1997) mapped the human GUCA2B gene to chromosome 1p34-p33.
Whitaker et al. (1997) demonstrated that the mouse Guca2b gene is tightly linked to the guanylin gene on mouse chromosome 4.
Kita et al. (1994) found that synthetic uroguanylin increased cGMP levels in T84 cells, competed for receptors with (125)I-labeled ST, and stimulated chloride secretion. Kita et al. (1994) discussed the bioactivity of human uroguanylin in light of their previous investigation of uroguanylin from opossum urine (Hamra et al., 1993).
Whitaker et al. (1997) noted that uroguanylin is an endogenous ligand of the intestinal receptor guanylate cyclase-C and stimulates an increase in cGMP, inducing chloride secretion via the cystic fibrosis transmembrane conductance regulator (CFTR; 602421). Although their structural homologies and similar bioactivities suggest that guanylin and uroguanylin are members of the same peptide family, their tissue gene expression patterns differ, indicating that they may have different roles in the regulation of epithelial functions.
Kinoshita et al. (1997) found significantly higher urinary excretion of uroguanylin in persons on a high-salt rather than a low-salt diet. In addition, their concentration of plasma uroguanylin increased with increasing serum creatinine, and the 10-kD precursor of uroguanylin increased as the severity of renal impairment increased. The findings suggested that uroguanylin is involved in the regulation of electrolyte homeostasis by the kidney.
In a review of the functions of uroguanylin, Forte et al. (1996) noted that uroguanylin receptors are present on the luminal surface of epithelial cells lining the intestinal tract and renal proximal tubules, leading to salt and water secretion into the intestinal lumen as well as the renal tubules. Uroguanylin mRNA is also expressed in both atria and ventricles of the heart. Since uroguanylin circulates in the plasma of normal individuals, it may function as an intestinal natriuretic hormone and its secretion may be influenced by dietary levels of salt.
Parikh et al. (2019) profiled single colonic epithelial cells from patients with inflammatory bowel disease (IBD; 266600) and unaffected controls and identified previously unknown cellular subtypes, including gradients of progenitor cells, colonocytes, and goblet cells, within intestinal crypts. At the top of the crypts, Parikh et al. (2019) found a previously unknown absorptive cell expressing the proton channel OTOP2 (607827) and the satiety peptide uroguanylin, that sensed pH and was dysregulated in inflammation and cancer.
Whitaker et al. (1997) speculated that uroguanylin and guanylin may represent gene duplications that have evolved to allow overlapping and complementary patterns of expression in the intestine.
Lorenz et al. (2003) found that transgenic uroguanylin knockout mice had in an impaired ability to excrete an enteral load of NaCl, primarily due to an inappropriate increase in renal Na+ absorption. They also had an increase in mean arterial blood pressure that was independent of the level of dietary salt intake. The authors concluded that uroguanylin plays a role in an enteric-renal communication axis in the maintenance of salt homeostasis in vivo.
Forte, L. R., Fan, X., Hamra, F. K. Salt and water homeostasis: uroguanylin is a circulating peptide hormone with natriuretic activity. Am. J. Kidney Dis. 28: 296-304, 1996. [PubMed: 8768930] [Full Text: https://doi.org/10.1016/s0272-6386(96)90318-2]
Hamra, F. K., Forte, L. R., Eber, S. L., Pidhorodeckyj, N. V., Krause, W. J., Freeman, R. H., Chin, D. T., Tompkins, J. A., Fok, K. F., Smith, C. E., Duffin, K. L., Siegel, N. R., Currie, M. G. Uroguanylin: structure and activity of a second endogenous peptide that stimulates intestinal guanylate cyclase. Proc. Nat. Acad. Sci. 90: 10464-10468, 1993. [PubMed: 7902563] [Full Text: https://doi.org/10.1073/pnas.90.22.10464]
Hess, R., Kuhn, M., Schulz-Knappe, P., Raida, M., Fuchs, M., Klodt, J., Adermann, K., Kaever, V., Cetin, Y., Forssmann, W.-G. GCAP-II: isolation and characterization of the circulating form of human uroguanylin. FEBS Lett. 374: 34-38, 1995. [PubMed: 7589507] [Full Text: https://doi.org/10.1016/0014-5793(95)01075-p]
Kinoshita, H., Fujimoto, S., Nakazato, M., Yokota, N., Date, Y., Yamaguchi, H., Hisanaga, S, Eto, T. Urine and plasma levels of uroguanylin and its molecular forms in renal diseases. Kidney Int. 52: 1028-1034, 1997. [PubMed: 9328941] [Full Text: https://doi.org/10.1038/ki.1997.424]
Kita, T., Smith, C. E., Fok, K. F., Duffin, K. L., Moore, W. M., Karabatsos, P. J., Kachur, J. F., Hamra, F. K., Pidhorodeckyj, N. V., Forte, L. R., Currie, M. G. Characterization of human uroguanylin: a member of the guanylin peptide family. Am. J. Physiol. 266: F342-F348, 1994. [PubMed: 8141334] [Full Text: https://doi.org/10.1152/ajprenal.1994.266.2.F342]
Lorenz, J. N., Nieman, M., Sabo, J., Sanford, L. P., Hawkins, J. A., Elitsur, N., Gawenis, L. R., Clarke, L. L., Cohen, M. B. Uroguanylin knockout mice have increased blood pressure and impaired natriuretic response to enteral NaCl load. J. Clin. Invest. 112: 1244-1254, 2003. [PubMed: 14561709] [Full Text: https://doi.org/10.1172/JCI18743]
Miyazato, M., Nakazato, M., Matsukura, S., Kangawa, K., Matsuo, H. Genomic structure and chromosomal localization of human uroguanylin. Genomics 43: 359-365, 1997. [PubMed: 9268639] [Full Text: https://doi.org/10.1006/geno.1997.4808]
Parikh, K., Antanaviciute, A., Fawkner-Corbett, D., Jagielowicz, M., Aulicino, A., Lagerholm, C., Davis, S., Kinchen, J., Chen, H. H., Alham, N. K., Ashley, N., Johnson, E., and 10 others. Colonic epithelial cell diversity in health and inflammatory bowel disease. Nature 567: 49-55, 2019. [PubMed: 30814735] [Full Text: https://doi.org/10.1038/s41586-019-0992-y]
Whitaker, T. L., Steinbrecher, K. A., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Cohen, M. B. The uroguanylin gene (Guca1b) is linked to guanylin (Guca2) on mouse chromosome 4. Genomics 45: 348-354, 1997. Note: Erratum: Genomics 66: 122 only, 2000. [PubMed: 9344659] [Full Text: https://doi.org/10.1006/geno.1997.4942]