Sandhya S. Visweswariah

Molecular Reproduction, Development & Genetics
Research Areas: 
Second messenger signal transduction in eukaryotes and prokaryotes
Research Highlights: 

The focus of research in the laboratory relates to signal transduction mediated by cyclic nucleotides. We investigate molecular mechanisms of signaling by receptor guanylyl cyclases, phosphodiesterases andnovel nucleotide cyclases in bacteria. We have been studying the regulation, expression and down-stream signaling events mediated by GC-C as well as looking into its expression in extra-intestinal tissues. During the course of these studies, we have performed mutational analysis of the protein kinase-like domain of GC-C, generated polyclonal and monoclonal antibodies to various domains of GC-C, investigated the mechanism of transcriptional regulation of the GC-C gene, and investigated the role of glycosylation of GC-C in terms of its regulation and ligand-binding properties. We have been interested in studying the regulation of the cGMP-binding, cGMP-specific phosphodiesterase (PDE5) in intestinal cells. PDE5 is the target for the drug sildenafil citrate, or Viagra, used in the treatment of male impotence. PDE5 is expressed in human colonic cells and in intestinal tissue and we have shown that its activity is regulated by intracellular cGMP levels in these cells, that increase on GCC activation. This presumably occurs through binding of cGMP to the GAF domains in the N-terminus of PDE5, resulting in allosteric activation of the enzyme. Our analysis of the genome of Mycobacterium tuberculosis indicates the presence of at least 16 putative Class III cyclases. We have initiated systematic biochemical and structural analysis of all Class III cyclases from M. tuberculosis. Using the existing structural and biochemical information on their eukaryotic counterparts, we have attempted to predict the status (whether active or not) and the substrate specificity (ATP vs GTP) of these proteins. In addition the association of the cyclase domain with several other protein domains points out the versatility of the cyclase domain. We have also recently identified,a novel cyclic AMP binding protein in these organisms which regulates portein lysine acetylation.