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Gene Review

Guca2a  -  guanylate cyclase activator 2a (guanylin)

Rattus norvegicus

Synonyms: GUANYL, Guanylate cyclase activator 2A, Guanylin, Guca2
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Disease relevance of Guca2a

  • Guanylin and E. coli heat-stable enterotoxin induce chloride secretion through direct interaction with basolateral compartment of rat and human colonic cells [1].
  • BACKGROUND & AIMS: Guanylin and heat-stable enterotoxin (STa) stimulate intestinal Cl- secretion via activation of the cystic fibrosis transmembrane regulator (CFTR)-encoded Cl- channel [2].
  • We now show that two assays previously used to examine the activity of purified beta gamma subunits--namely, to support either rhodopsin-catalyzed guanyl nucleotide exchange on Gt alpha or pertussis toxin-catalyzed ADP-ribosylation of Gt alpha--can be used with detergent extracts of cells [3].
  • Complementary DNAs encoding three subtypes of the alpha subunit (alpha i-1, alpha o and alpha s) of rat guanyl nucleotide regulatory proteins were used to construct recombinant baculoviruses which direct high-level expression of the corresponding proteins in cultured Sf9 insect cells [4].
  • Moreover, guanylin induced intense edema in the mucosa and submucosa of the small intestine 5 min after the injection, which disappeared after 30 min [5].

High impact information on Guca2a


Chemical compound and disease context of Guca2a


Biological context of Guca2a

  • This peptide, which we have termed guanylin, is composed of 15 amino acids and has the following amino acid sequence, PNTCEICAYAACTGC, as determined by automated Edman degradation sequence analysis and electrospray mass spectrometry [14].
  • Transfection of COS-7 cells with the guanylin cDNA resulted in the expression of a secreted protein of M(r) 10,000 [15].
  • Because guanylin circulates in the bloodstream, we tested the hypothesis that it modulates intestinal ion transport by acting on the serosal side of intestinal cells [1].
  • In the duct cells guanylin immunoreactivity spread after the duct system developed, whereas in acinar cells it disappeared after cell differentiation [16].
  • Guanylin-stimulated HCO3- secretion was independent of luminal Cl-, inhibited by the Cl- channel blocker 5-nitro-2-(3-phenylpropylamino)-benzoate, and additive to the HCO3- secretory rate stimulated by glucagon and carbachol but not by the tested adenosine 3',5'-cyclic monophosphate (cAMP)-dependent agonists [2].

Anatomical context of Guca2a

  • Guanylyl cyclase C, the apparent guanylin receptor, was found in abundant amounts in the intestine by Northern analysis, and by the polymerase chain reaction or cDNA cloning it was also found in adrenal gland, airway epithelial cells, brain, and olfactory and tracheal mucosa [15].
  • Guanylin mRNA was prevalent in rat intestine but was also found in low abundance in adrenal gland, kidney, and uterus/oviduct [15].
  • We previously detected specific binding activity of Escherichia coli heat-stable enterotoxin (ST), the guanylin exogenous ligand, in rat colonic basolateral membranes [1].
  • Guanylin addition to either side of Caco-2 cells induced the same effects as ST, although to a lesser extent [1].
  • Clones have been isolated which demonstrate that the guanylin peptide is contained within a 115 amino acid apparent preprohormone encoded by a 600 base messenger RNA in rat jejunum [17].

Associations of Guca2a with chemical compounds

  • Guanylin: an endogenous activator of intestinal guanylate cyclase [14].
  • Guanylin required oxidation for expression of bioactivity and subsequent reduction of the oxidized peptide eliminated the effect on cyclic GMP, indicating a requirement for cysteine disulfide bond formation [14].
  • The expressed proguanylin failed to elevate cyclic GMP concentrations in human colonic T84 cells, but acetic acid treatment of pro-guanylin activated it and resulted in large elevations of cyclic GMP [15].
  • The carboxyl-terminal region of the predicted polypeptide contained a sequence identical to guanylin, but the 15-amino acid peptide likely represents an artifact of previous acetic acid extraction methods, since an aspartate residue precedes the amino-terminal proline [15].
  • Guanylin strongly stimulates rat duodenal HCO3- secretion: proposed mechanism and comparison with other secretagogues [2].

Physical interactions of Guca2a

  • Endothelin receptor subtypes are coupled to adenylate cyclase via different guanyl nucleotide-binding proteins in vasculature [18].
  • Furthermore, our data clearly show that an accelerating AMPA receptor endocytosis by stimulating the formation of guanyl nucleotide dissociation inhibitor-Rab5 complex is a potential downstream processing of p38 MAPK activation to mediate DHPG-LTD [19].
  • A growing body of evidence suggests a role for guanyl nucleotide binding proteins (G proteins) in GnRH action [20].
  • Regulation of thyrotropin-releasing hormone binding by monovalent cations and guanyl nucleotides [21].
  • The results suggest a role of the regulatory guanyl nucleotide-binding protein in diabetes leading to an increased dose response relationship of the hepatic adenylate cyclase system to glucagon [22].

Regulatory relationships of Guca2a

  • It is concluded that occupancy of the guanyl nucleotide binding site that activates the catalytic moiety of the system is not sufficient to promote hormone-receptor coupling to adenylyl cyclase and that occupancy of a second site by guanyl nucleotides is essential to effect stimulation of adenylyl cyclase by the glucagon-receptor complex [23].
  • CRF stimulates adenylate cyclase activity at least partly through a guanyl nucleotide-dependent mechanism [24].
  • Binding of thyrotropin-releasing hormone (TRH) to specific receptors on membranes isolated from GH4C1 pituitary cells was inhibited by monovalent cations and guanyl nucleotides [21].
  • We conclude that calmodulin influences the activity of the guanyl nucleotide-dependent adenylate cyclase in rat thymocytes and ultimately mediates the stimulation of enzyme activity that T3 produces [25].
  • Guanyl nucleotides failed to influence the KD and Bmax parameters of [3H]WAY-100635 binding to 5-HT1A receptors [26].

Other interactions of Guca2a


Analytical, diagnostic and therapeutic context of Guca2a

  • RESULTS: By every criterion, the low-salt diet reduced expression of guanylin to 30%-40% of the level found in control animals [29].
  • Western blotting analyses in hypophyseal tissue extracts identified the expected 12.5-kDa immunoreactive peptide by using two different region-specific guanylin antisera [30].
  • Since the latter protein is also expressed in airway epithelia, we investigated the lung of three mammalian species for the presence and cellular localization of guanylin by immunoblot (Western blot) analyses and light and electron microscopical immunocytochemistry [31].
  • Synthetic uroguanylin-(2-15) (i.e., EDCELCINVACTGC) was 10-fold more potent than synthetic rat guanylin, but both peptides were less potent than Escherichia coli ST in the T84 cell cGMP bioassay [32].
  • Guanylin was localized to secretory granules underneath the apical membrane of Clara cells and was, in addition, detected in high concentrations in bronchoalveolar lavage fluid, predicting release of the peptide luminally into the bronchiolar airways [33].


  1. Guanylin and E. coli heat-stable enterotoxin induce chloride secretion through direct interaction with basolateral compartment of rat and human colonic cells. Albano, F., de Marco, G., Canani, R.B., Cirillo, P., Buccigrossi, V., Giannella, R.A., Guarino, A. Pediatr. Res. (2005) [Pubmed]
  2. Guanylin strongly stimulates rat duodenal HCO3- secretion: proposed mechanism and comparison with other secretagogues. Guba, M., Kuhn, M., Forssmann, W.G., Classen, M., Gregor, M., Seidler, U. Gastroenterology (1996) [Pubmed]
  3. Defective guanyl nucleotide-binding protein beta gamma subunits in a forskolin-resistant mutant of the Y1 adrenocortical cell line. Mitchell, J., Northup, J.K., Schimmer, B.P. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  4. Baculovirus expression of mammalian G protein alpha subunits. Labrecque, J., Caron, M., Torossian, K., Plamondon, J., Dennis, M. FEBS Lett. (1992) [Pubmed]
  5. Intravenous injection of guanylin induces mucus secretion from goblet cells in rat duodenal crypts. Furuya, S., Naruse, S., Hayakawa, T. Anat. Embryol. (1998) [Pubmed]
  6. The molecular basis of hypertension. Garbers, D.L., Dubois, S.K. Annu. Rev. Biochem. (1999) [Pubmed]
  7. RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. Ebinu, J.O., Bottorff, D.A., Chan, E.Y., Stang, S.L., Dunn, R.J., Stone, J.C. Science (1998) [Pubmed]
  8. Uroguanylin is expressed by enterochromaffin cells in the rat gastrointestinal tract. Perkins, A., Goy, M.F., Li, Z. Gastroenterology (1997) [Pubmed]
  9. Pertussis toxin reverses the inhibition of insulin secretion caused by [Arg8]vasopressin in rat pancreatic islets. Khalaf, L.J., Taylor, K.W. FEBS Lett. (1988) [Pubmed]
  10. Involvement of Ni protein in the functional coupling of the atrial natriuretic factor (ANF) receptor to adenylate cyclase in rat lung plasma membranes. Resink, T.J., Panchenko, M.P., Tkachuk, V.A., Bühler, F.R. Eur. J. Biochem. (1988) [Pubmed]
  11. gamma-Hydroxybutyrate receptor binding in rat brain is inhibited by guanyl nucleotides and pertussis toxin. Ratomponirina, C., Hodé, Y., Hechler, V., Maitre, M. Neurosci. Lett. (1995) [Pubmed]
  12. Effects of guanyl nucleotides on CCKB receptor binding in brain tissue and continuous cell lines: a comparative study. Kaufmann, R., Schöneberg, T., Henklein, P., Meyer, R., Martin, H., Ott, T. Neuropeptides (1995) [Pubmed]
  13. Studies on pyrazinoylguanidine. 3. Downregulation of lipolysis in isolated adipocytes. A-Rahim, Y.I., Beyer, K.H., Vesell, E.S. Pharmacology (1996) [Pubmed]
  14. Guanylin: an endogenous activator of intestinal guanylate cyclase. Currie, M.G., Fok, K.F., Kato, J., Moore, R.J., Hamra, F.K., Duffin, K.L., Smith, C.E. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  15. Cloning and expression of guanylin. Its existence in various mammalian tissues. Schulz, S., Chrisman, T.D., Garbers, D.L. J. Biol. Chem. (1992) [Pubmed]
  16. Ontogeny of guanylin-immunoreactive cells in rat salivary glands. Vaccaro, R., Cetin, Y., Renda, T.G. Anat. Embryol. (2004) [Pubmed]
  17. Rat guanylin cDNA: characterization of the precursor of an endogenous activator of intestinal guanylate cyclase. Wiegand, R.C., Kato, J., Currie, M.G. Biochem. Biophys. Res. Commun. (1992) [Pubmed]
  18. Endothelin receptor subtypes are coupled to adenylate cyclase via different guanyl nucleotide-binding proteins in vasculature. Eguchi, S., Hirata, Y., Imai, T., Marumo, F. Endocrinology (1993) [Pubmed]
  19. Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. Huang, C.C., You, J.L., Wu, M.Y., Hsu, K.S. J. Biol. Chem. (2004) [Pubmed]
  20. Cholera toxin and pertussis toxin provoke differential effects on luteinizing hormone release, inositol phosphate production, and gonadotropin-releasing hormone (GnRH) receptor binding in the gonadotrope: evidence for multiple guanyl nucleotide binding proteins in GnRH action. Hawes, B.E., Barnes, S., Conn, P.M. Endocrinology (1993) [Pubmed]
  21. Regulation of thyrotropin-releasing hormone binding by monovalent cations and guanyl nucleotides. Hinkle, P.M., Kinsella, P.A. J. Biol. Chem. (1984) [Pubmed]
  22. Increased dose-response relationship of liver plasma membrane adenylate cyclase to glucagon stimulation in diabetic rats. A possible role of the guanyl nucleotide-binding regulatory protein. Allgayer, H., Bachmann, W., Hepp, K.D. Diabetologia (1982) [Pubmed]
  23. Coupling of glucagon receptor to adenylyl cyclase. Requirement of a receptor-related guanyl nucleotide binding site for coupling of receptor to the enzyme. Iyengar, R., Swartz, T.L., Birnbaumer, L. J. Biol. Chem. (1979) [Pubmed]
  24. Multiple factors involved in the control of ACTH and alpha-MSH secretion. Proulx-Ferland, L., Meunier, H., Côté, J., Dumont, D., Gagné, B., Labrie, F. J. Steroid Biochem. (1983) [Pubmed]
  25. Calmodulin mediates the stimulatory effect of 3,5,3'-triiodothyronine on adenylate cyclase activity in rat thymocyte plasma membranes. Segal, J., Rehder, M.C., Ingbar, S.H. Endocrinology (1986) [Pubmed]
  26. Characterisation of the binding of [3H]WAY-100635, a novel 5-hydroxytryptamine1A receptor antagonist, to rat brain. Khawaja, X., Evans, N., Reilly, Y., Ennis, C., Minchin, M.C. J. Neurochem. (1995) [Pubmed]
  27. Expression and characterization of gastrin-releasing peptide receptor in normal and cancerous pancreas. Hajri, A., Koenig, M., Balboni, G., Damgé, C. Pancreas (1996) [Pubmed]
  28. Regional stimulatory and inhibitory effects of guanine nucleotides on [125I]galanin binding in rat brain: relationship with the rate of occupancy of galanin receptors by endogenous galanin. Lagny-Pourmir, I., Epelbaum, J. Neuroscience (1992) [Pubmed]
  29. Low salt intake down-regulates the guanylin signaling pathway in rat distal colon. Li, Z., Knowles, J.W., Goyeau, D., Prabhakar, S., Short, D.B., Perkins, A.G., Goy, M.F. Gastroenterology (1996) [Pubmed]
  30. Expression of guanylin in "pars tuberalis-specific cells" and gonadotrophs of rat adenohypophysis. D'Este, L., Kulaksiz, H., Rausch, U., Vaccaro, R., Wenger, T., Tokunaga, Y., Renda, T.G., Cetin, Y. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  31. Bronchiolar nonciliated secretory (Clara) cells: source of guanylin in the mammalian lung. Cetin, Y., Kulaksiz, H., Redecker, P., Bargsten, G., Adermann, K., Grube, D., Forssmann, W.G. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  32. Uroguanylin: structure and activity of a second endogenous peptide that stimulates intestinal guanylate cyclase. 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. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  33. Clara cell impact in air-side activation of CFTR in small pulmonary airways. Kulaksiz, H., Schmid, A., Hönscheid, M., Ramaswamy, A., Cetin, Y. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
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