Research

Our research is focused on the analysis of structure-function relationship and signal transduction mechanisms of the angiotensin II (Ang II) receptors. Ang II is an octapeptide hormone, master regulator of blood pressure, salt-water balance, steroid genesis, reactive oxygen production, proliferative response and matrix deposition. Two isoforms of Ang II receptors; AT1 and AT2, both members of the G-protein-coupled receptor (GPCR)-superfamily mediate these responses. In addition to G-protein-cou­pled responses, the AT1 receptor initiates intracellular signal transduction pathways that are usually activated by cytokine and growth factor receptors. The AT2 receptor mediates differentiation, inhibition of growth and apoptosis of cells.

The AT1 receptor is the prototype for peptide hormone GPCRs. It contains a cytoplasmic domain that primarily binds and activates the G-protein, interacts with different kinases and adapter proteins that act as signaling platforms. The extracellular domain, in combination with the seven-transmembrane helical bundle, binds Ang II and clinically important selective antihypertensive drugs.

Our past structure-function studies defined the interaction of ligands and the G-protein with these receptors and demonstrated allosteric regulation across the membrane barrier. We have reported novel a mechanism, ligand induced selectivity in signaling, a pharmacological phenomenon that alludes to distinct conformation mechanisms for intramolecular communication between the two functional domains situated on the opposite sides of the membrane.

Current studies of the AT1 receptors are aimed at elucidating: (i) specific conformational changes that govern activation and inhibition of AT1 receptor leading to G-protein coupling as well as coupling to G-protein independent molecules, (ii) molecular mechanisms of G-protein independent signaling, and (iii) receptor-induced post-translational modification of signaling proteins. To understand in vivo consequence of "chronic activation" of the AT1 receptor, we have developed transgenic mouse models expressing wild-type and constitutively activated mutant AT1 receptors. These mouse models are in use for understanding: (i) mechanisms of retrograde signaling from plasma membrane to nucleus; (ii) Ang II regulated chromatin remodeling; (iii) epigenetic alterations induced by Ang II in vivo and (v) profiling gene expression changes associated with hypertrophy.

The AT2 receptor is an important regulator of physiological ontogenesis in the developing fetus and tissue-remodeling in the adult. Familial mutations in the AT2 receptor gene cause congenital abnormality of kidney and urinary tract  in humans. The AT2 receptor is upregulated in failing and infracted hearts, in neointima formation after vascular injury, in atretic ovarian follicles, in uterine endometrium and in healing skin wounds. In most instances the high levels of AT2 receptor re-expression is localized to remodeling sites. We have obtained evidence that de novo overexpression of the AT2 receptor induces apoptosis. The AT2 receptor cytoplasmic domain interacts with novel molecules to induce apoptosis. The goal of AT2 receptor research is to identify the components and signal transduction mechanisms leading to apoptosis. We use directed proteomic analysis by mass-spectrometry to accomplish this goal.