The roles of cGMP and receptor guanylyl cyclase C in the gut: diarrhoea, inflammation and cancer

Professor Sandhya S. Visweswariah; Indian Institute of Science, Bengaluru, India

Sandhya S. Visweswariah is an Honorary Professor, in the Department of Developmental Biology and Genetics at the Indian Institute ofScience. She is currently a Provost’s Visiting Professor at Imperial College London. She has spent her research career working on cyclicnucleotide signalling in prokaryotes and eukaryotes. She is a member of the Indian National Science Academy, the Indian Academy of Science and The World Academy of Sciences. She has received an HFSP Short-Term Fellowship, and Fulbright-Nehru Senior Research Fellowship. She has received funding from the Royal Society through a Collaborative Grant for Research Professors, the WellcomeTrust-DBT India Alliance, and NIH/NIAID. Her interests are in biochemistry and signal transduction in the context of gut physiology.

Diarrhoeal disease and inflammatory bowel disease (IBD) are the most common disorders of the gut. Fluid and ion secretion in the gut is regulated by both cAMP and cGMP, and in this talk, I will focus on the role of a receptor guanylyl cyclase, GC-C. This protein is the product of the GUCY2C gene. The protein product is evolutionarily conserved, with orthologues found in worms, fruit flies, fish, and primates. GC-C is the target of the gastrointestinal hormones guanylin and uroguanylin and bacterial heat-stable enterotoxins that are a major cause of watery diarrhoea. Mutations in GUCY2C are associated with familial secretory diarrhoea that manifests in symptoms that mimic Crohn’s Disease and ulcerative colitis. I will talk about our understanding of the biology of GC-C in the context of signalling within the intestinal epithelial cells and in mouse models that harbour an activating mutation in the receptor equivalent to that seen in human patients with congenital secretory diarrhoea. Through careful molecular analysis of the changes seen in the gut of knock-in mice, we identify several novel pathways regulated by cGMP in the gut, which could provide opportunities for therapeutic intervention in the future.