Srinivas Tipparaju, PhD

Instructor of Medicine

Research Interests:

The focus of my research is to elucidate the mechanisms for redox regulation of ion channels. Ischemia or hypoxia leads to redox imbalances in the heart and causes detrimental changes that lead to dysfunction of the heart. The tight balance of NADPH/NADP⁺ or NADH/NAD⁺ ratios in cardiomyocytes is vital for cardiac function. The relationship between hypoxia-induced changes in pyridine nucleotides and Kv channels is a major area of my research. The Kvβ-subunit (AKR6) belongs to the aldo-keto reductases superfamily and displays tight binding to pyridine nucleotides. The Kvβ-subunit binds different Kv channels (Kv1 and Kv4) and modulates its kinetics and gating properties, but the precise mechanism and its physiological meaning is unclear. We have demonstrated that voltage-gated potassium channels, which maintain the resting membrane potential and the shape of action potential, are differentially regulated by pyridine nucleotides. Based on these observations, we hypothesized that Kvβ-subunits can impart a redox-sensing property to Kv channels. In previous studies using site-directed mutagenesis approach, we abolished the binding of pyridine nucleotides to the Kvβ-subunit and demonstrated that Kv channel inactivation is regulated as a function of pyridine nucleotides present in the cell. Recently, we identified the obligatory role of the C-terminus of the Kv channel in sensing the pyridine nucleotides bound to the Kvβ-subunit. Based on these studies, I am developing new lines of enquiry for which I will elucidate the role of the Kvβ-subunit in various pathological states. The β-subunits of the voltage-gated potassium channels seem to have a unique and important role in cardiac arrhythmogenesis, and my research is focused on understanding the role of the β-subunit. I believe that understanding these mechanisms can provide potential new therapeutics for the treatment of heart disease and stroke.

Journal Articles:

Tipparaju SM, Barski O, Srivastava S, Bhatnagar A. Catalytic mechanism and substrate specificity of the beta-subunit of the voltage-gated potassium channel. Biochemistry. 2008 47, 8840-54.

Tipparaju SM, Liu SQ, Barski OA, Bhatnagar A. NADPH binding to b-subunit regulates inactivation of voltage-gated K⁺ channels. Biochem Biophys Res Commun. 2007, 359, 269-76. 

Tipparaju SM, Saxena N, Liu SQ, Kumar R, Bhatnagar A. Differential regulation of voltage-gated K⁺ channels by oxidized and reduced pyridine nucleotide coenzymes. Am J Physiol Cell Physiol. 2005, 288, C366-76.