Guanylins

Definition
Guanylins are small, heat-stable peptides that bind to and activate Guanylyl cyclase-C (GC-C) receptors to regulate intestinal and renal fluid and electrolyte transport through secondary messenger, cyclic guanosine 39,59-monophosphate (cGMP)1.

Related peptides
The guanylin family of cGMP-regulating peptides has three subclasses of peptides containing either three intramolecular disulfides found in bacterial heat-stable enterotoxins (ST), or two disulfides observed in guanylin and uroguanylin, or a single disulfide exemplified by lymphoguanylin2. The major endogenous guanylin molecule in human intestine and plasma is 10-kDa proguanylin, 15-amino acid guanylin being a minor component. Human guanylin is distributed widely from the duodenum to colon, the highest contents being in the ileum and proximal colon3.

Discovery
Guanylin and uroguanylin are novel peptides that were first isolated from rat jejunum and opossum urine, respectively. Guanylin was purified and sequenced using automated Edman degradation sequence analysis and electrospray mass spectrometry by Currie et al in 19914.

Structural characteristics
The circulating hormonal form of guanylin is around 10.3-kDa5. Human GN consists of 15 amino acids and possesses two disulfide bonds between the cysteins in positions 4 to 12 and 7 to 15. Human UGN consists of 16 amino acids and also has two disulfide bonds at the same positions. These disulfide bonds are essential for the activity of the peptides6.

Mechanism of action
Two receptor GC signaling molecules have been identified that are highly expressed in the intestine (GC-C) and/or the kidney (OK-GC) and are selectively activated by the guanylin peptides. Stimulation of cGMP production in renal target cells by guanylin peptides in vivo or ex vivo elicits a long-lived diuresis, natriuresis, and kaliuresis. Activation of GC-C receptors in target cells of intestinal mucosa markedly stimulates the transepithelial secretion of Cl and HCO 3, causing enhanced secretion of fluid and electrolytes into the intestinal lumen. Bacterial ST peptides act as mimics of guanylin and uroguanylin in the intestine, which provide a cellular mechanism underlying the diarrhea caused by ST-secreting strains of Escherichia coli2.

Function
The Guanylin family of peptides is involved in the pathophysiology of some gastrointestinal, renal and heart diseases. Guanylin and uroguanylin may participate in a novel endocrine axis linking the digestive system and kidney as a physiological mechanism that influences Na+ homeostasis. Guanylin, uroguanylin, and/or lymphoguanylin may also serve within intrarenal signaling pathways controlling cGMP production in renal target cells. It has been proposed that guanylin regulatory peptides participate in a complex multifactorial biological process that evolved to regulate the urinary excretion of NaCl when dietary salt levels exceed the body's physiological requirements. This highly inGuanylinstegrated and redundant mechanism allows the organism to maintain sodium balance by eliminating excess NaCl in the urine2.

References
1.Nakazato M (2001). Guanylin family: new intestinal peptides regulating electrolyte and water homeostasis. J Gastroenterol, 36:219–225.
2.Forte LR, London RM, Freeman RH, Krause WJ(2000). Guanylin peptides: renal actions mediated by cyclic GMP. Am J Physiol Renal Physiol 278 (2):180-191.
3.Nakazato M, Yamaguchi H, Shiomi K, Date Y, Fujimoto S, Kangawa K, Matsuo H, Matsukura S (1994). Identification of 10-kDa proguanylin as a major guanylin molecule in human intestine and plasma and its increase in renal insufficiency. Biochem Biophys Res Commun. 205(3):1966-1975.
4.Kuhn M, Raida M, Adermann K, Schulz-Knappe P, Gerzer R, Heim JM, Forssmann WG (1993). The circulating bioactive form of human guanylin is a high molecular weight peptide.FEBS Lett, 318(2): 205-209.
5.Sindic A, Schlatter E(2006).Cellular Effects of Guanylin and Uroguanylin. J Am Soc Nephrol,17(3):607-616.
6.Currie MG, Fok KF, Kato J, Moore RJ, Hamra FK, Duffin KL, Smith CE(1992). Guanylin: an endogenous activator of intestinal guanylate cyclase. Proc Natl Acad Sci U S A, 3: 947-951.