Gut reactions and gut instincts: the role of cGMP

Abstract:

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 of 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 that is 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 that are regulated by cGMP in the gut, which could provide opportunities for therapeutic intervention in the future.

Background Information:

Sandhya Visweswariah is one of India's leading cell signalling researchers and has undertaken original work on deciphering signal transduction pathways mediated by cyclic cGMP nucleotides and their roles in microbiology and mediating inflammatory bowel disease. Sandhya is based at the Institute of Science, Bangalore, India. She is currently the Chairperson of the Department of Molecular Reproduction, Development and Genetics and the Co-chair of the Centre for Biosystems Science and Engineering.

Sandhya is currently visiting the UK as a Provost’s Visiting Professorship of Biochemistry at Imperial College London. See for further information (https://www.imperial.ac.uk/news/249318/introducing-professor-sandhya-visweswariah/)

Sandhya’s work I of the highest quality and is multidisciplinary involving a blend of biochemistry, structural biology and high-level physiological microbiology and mouse model analysis. It is relevant to understanding how bacteria in our gut impact a wide range of human disease including inflammatory bowel disease, colorectal cancer, and obesity.

The work of Sandhya, that I am most familiar with involves analysis of pseudokinase (or kinase-like) domain that is found in specialised receptor guanylyl cGMP cyclases. Mutations that lie in the kinase-like domain of these receptors are associated with various human disease including inflammatory bowel disease. These mutations either abolish or enhance cGMP production by these receptors to alter downstream signalling events. This raises the interesting possibility that one could identify molecules that bind to the pseudokinase domain and regulate the activities of these receptors, to alleviate symptoms in patients harbouring these mutations.

Sandhya has received a number of prestigious awards including being elected to the Indian National Academy of Sciences. She is a Fellow of the world academy of sciences and received a Rustom Choksi Award by the Indian Institute of Science.

She has devoted an enormous amount of time to build up a vibrant research centre at the Bangalore Indian Science Centre.