Guanylins

Introduction

The guanylin family of bioactive peptides include three endogenous peptides, including guanylin, lymphoguanylin and uroguanylin, and one exogenous peptide toxin produced by enteric bacteria. Guanylin peptides are related to the intestinal diseases such as diarrhea and colon cancer, and cardiac disorders or chronic renal diseases such as the congestive heart failure where guanylin and/or uroguanylin levels in the circulation and/or urine are pathologically elevated. Guanylin peptides are clearly involved in the regulation of salt and water homeostasis. Further study revealed that in addition to those previously documented for control of intestinal and renal function, these novel peptides have diverse physiological roles.

Mechanism of Action

The small cysteine-rich peptides of guanylin family activate cell-surface receptors with the intrinsic guanylate cyclase activity, which can modulate cellular function via the intracellular second messenger, cyclic GMP. Guanylin and uroguanylin have similar actions in the intestine to stimulate transepithelial secretion of Cl^- and HCO₃^- anions, providing the physiological driving force for secretion of Na⁺ and water into the intestine. Besides, studies indicate that these peptides interact with a common set of receptors located on enterocytes lining the intestinal lumen. The finding that a neuroendocrine cell model responds to guanylin with increased secretion of both γ-aminobutyric acid and chromogranin A provided a plausible mechanism for plasma guanylin-mediated stimulation of intestinal secretion.

Application of Guanylins

Produced within the intestinal mucosa, guanylin serves in a paracrine mechanism for regulation of intestinal fluid and electrolyte secretion. In addition to the established mechanisms for cGMP-mediated control of intestinal fluid and electrolyte secretion, it is likely that guanylin peptides have other physiological actions in the digestive system. It has been reported that guanylin peptides are related to the secretory diarrhea, kidney diseases, respiratory disorders and colon cancer. Uroguanylin is postulated to serve in an endocrine axis linking the GI and renal organ systems for regulation of salt and water excretion by the kidney to help maintain body Na⁺ balance. Besides, guanylin may have endocrine actions. Therefore, the measurement of circulating levels of the peptides provides useful information pertaining to possible endocrine mechanisms for these peptides. Experiments revealed that guanylin gene expression is significantly downregulated in colon cancer. The normal mucosa adjacent to colon tumors has abundant amounts of guanylin mRNA transcripts indicating that guanylin expression is inhibited in colon tumor cells. Research suggests that guanylin peptides may have potential for therapeutic applications in the treatment of cystic fibrosis.

References

1. Forte, L. R. (1999). Guanylin regulatory peptides: structures, biological activities mediated by cyclic GMP and pathobiology. Regulatory peptides, 81(1-3), 25-39.
2. Fonteles, M. C., & do Nascimento, N. R. F. (2011). Guanylin peptide family: history, interactions with ANP, and new pharmacological perspectives. Canadian journal of physiology and pharmacology, 89(8), 575-585.
3. Forte, L. R., & Currie, M. G. (1995). Guanylin: a peptide regulator of epithelial transport. The FASEB journal, 9(8), 643-650.