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  • br Acknowledgements br Funding This work was supported


    Funding: This work was supported by the Instituto Nacional de Biomedicina do Semiárido (INCT-IBISAB-CNPq), Edital MCT/CNPq N° 014/2010 - Universal and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
    Introduction Guanylin and uroguanylin are small, heat-stable cyclic peptides comprising 15–19 amino acids (aa.s), which stimulate Cl− and therefore fluid secretion within the intestine and certain renal tubules (Forte, 2003, Forte, 2004). Both peptides are synthesised and stored as much larger 115–116 aa. prohormones within specific endocrine cells throughout the entire length of the intestine of all mammals so far investigated and are released into the intestinal lumen or the blood in their precursor forms in response to ingested salt loads (Kita et al., 1999, Moss et al., 2008). The active C-terminal peptides are liberated from the prohormones by as yet unknown extracellular proteases within the intestinal lumen or the kidney tubule. Together with the related peptide lymphoguanylin, which has so far only been isolated from the opossum spleen, they mediate Cl−, HCO3− and fluid secretion in the intestine (Sindic and Schlatter, 2006) and Na+, K+, Cl− and fluid secretion in renal tubules (Fonteles et al., 1998) by activating membrane associated guanylate cyclase C (GC-C), increasing intracellular cGMP with subsequent activation of protein kinase G II (PKG). In mammals, GC-C is a member of a family of seven related particulate guanylate cyclases that are specifically expressed within different tissue types, which possess similar amino Ritonavir sequences and therefore certain common structural and functional features (see Yamagami and Suzuki, 2005 and Garbers et al., 2006 for reviews). The membrane guanylate cyclases are activated by different mechanisms but three classes, GCs A, B and C, are activated by the binding of specific extracellular cyclic peptides. In most tissues, the activation of the cGMP signalling pathway also signals the increase in cAMP levels within the cells by inhibition of cAMP-dependent phosphodiesterase III and, in intestinal enterocytes, both PKG and protein kinase A (PKA) suppress Na+ absorption by inhibition of the Na+/H+ exchanger and mediate Cl− and HCO3− secretion by phosphorylation and activation of the apically located cystic fibrosis transmembrane conductance regulator (CFTR), which in these epithelial cells functions as a low conductance Cl− channel (Sindic and Schlatter, 2006). The transepithelial secretion of Cl− is accompanied by a paracellular movement of Na+ powered by the electrical gradient created by the initial anion transport. The subsequent movement of water via either paracellular or transcellular, aquaporin-mediated, pathways completes the net fluid secretion across the epithelium. In addition to a role in fluid secretion the guanylin/uroguanylin/GC-C signalling system has been implicated in the regulation of enterocyte growth and maturation and consequently their anti-prolific actions suggest that the peptides and their signalling system may serve a protective role against the incidence and generation of certain colorectal cancers (Sindic and Schlatter, 2006, Camici, 2008). The guanylin/GC-C signalling system has been described within the gastrointestinal tract of a variety of species with both the peptides and their receptors being cloned from teleost (Comrie et al., 2001a, Comrie et al., 2001b, Yuge et al., 2003, Yuge et al., 2006, Cramb et al., 2005, Nakauchi and Suzuki, 2005) and elasmobranch (unpublished observations) fish. Within anguillid species a third guanylin-like peptide, named renoguanylin has been identified which exhibits high levels of expression in both the intestine and the kidney (Yuge et al., 2003). In addition, two isoforms of the GC-C receptor (termed GC-C1 and GC-C2) have also been reported (Comrie et al., 2001b, Yuge et al., 2006). These multiple copies of the peptides and receptors are undoubtedly the result of the extra gene duplication event that arose within the teleost fish lineage (Christoffels et al., 2004, Hoegg et al., 2004; Semon and Wolfe, 2007).