Question

Compare and contrast the defect in signaling of 5-HT (serotonin) in the gut causing IBS and the WNT signaling pathway leading to cancers like familial adenomatous polyposis.

Answer 1

One of the most worked out defects reported in IBS (Irritable bowel syndrome) is the altered availability of 5-HT (serotonin) in the gut. Within the gut, serotonin acts as a paracrine factor and plays a important role in gut motility.  Alterations in its concentration alters the gut mobility and therefore the syndrome. One of the most prevalent cause of this is a lowered level of serotonin‐selective reuptake transporter (SERT). SERTs are responsible for clearing 5-HT from the intestinal lumen and therefore a lowered level of SERT have a profound effect in the availability of 5-HT and therefore the symptoms reported in IBS.

WNT signalling causes an accumulation of beta-catennin in the cytoplasm, which eventually gets translocated to the nucleus and causes transcription of genes, a subset of which is involved in promoting cell division. Intracellular beta- catennin levels are put to check by few proteins, one of which is the APC (Adenomatous polyposis coli) which targets it for ubiquitination and proteasomal degradation. In response to Wnt siganlling the degrading complexes including the ones involving APC is removed leading to beta- catennin accumulation. A mutation in the APC gene that makes it non-functional would therefore lead to increased beta-catennin induced transcription of cell division protein genes and polyp formation, which is the hallmark of the familial adenomatous polyposis.

Similarities in these two process is that in both defects in the signalling of a paracrine factor is the underlying cause. While for IBS, it is 5-HT, for familial adenomatous polyposis, it is wnt. In both cases an upregulation of the pathways takes place. However, a major difference between the two is that while in IBS there is a prolonged availability of the ligand (5-HT) itself that makes the pathway upregulated, in familial adenomatous polyposis, the underlying cause is a mutation in a downstream signalling factor which makes it non-functional. Wnt signalling decreases this factor and therefore a non-functional mutation in APC gene, means a perpetual activation of the wnt-pathway.