Beta-adrenergic receptors (beta-ARs) belong to a family of seven transmembrane receptors, also known as the G-protein coupled receptors (GPCRs), that form the interface between the sympathetic nervous system and the cardiovascular system. Beta-ARs are one of the most powerful regulators of cardiac function that are chronically desensitized and downregulated in conditions of heart failure, in part, due to increased phosphorylation of beta-ARs by beta-adrenergic receptor kinase 1 (beta-ARK1). Beta-ARK1 forms a cytosolic complex with phosphoinositide 3-kinase (PI3K) and targets PI3K to the receptor complex following agonist stimulation. Beta-ARK1 targeted PI3K activity at the receptor complex is required for beta-AR internalizaton, as expression of inactive PI3K attenuates receptor internalization. Importantly, cardiac-specific overexpression of inactive PI3K ameliorates cardiac dysfunction in mouse models of heart failure by blocking the receptor of internalization, which seems to result in the preservation of beta-AR function. The underlying mechanism by which preservation of beta-AR function occurs is currently unknown. Identifying the mechanism by which PI3K regulates these protein(s) involved in the preservation of beta-AR function would allow us to develop novel therapeutic interventions for heart failure, or alternatively, could complement the current treatments. We are using a combination of proteomics, transgenic mouse models, and cell culture systems to comprehensively investigate and elucidate the underlying molecular mechanism.
Manveen K Gupta Ph.D.
Maradumane L Mohan PhD
Sromona Mukherjee Ph.D.
Postdoctoral Research Fellow
Anita Sahu Ph.D.
- Mohan, M. L., Jha, B.K., Gupta, M.K., Vasudevan, N.T., Martelli, E.E., Mosinski, J.D., Naga Prasad, S.V. (2013). Phosphoinositide 3-Kinase g inhibits cardiac GSK-3 Independent of Akt. Science Signaling 6(259):ra4 (Cover page article).
- Mohan, M.L., Vasudevan, N.T., Gupta, M. K., Martelli, E.E. and Naga Prasad, S.V. (2012). G-protein coupled receptor resensitization – appreciating the balancing act of receptor function. Current Molecular Pharmacology, 5: 317-401.
- Vasudevan, N.T., Mohan, M.L., Goswami, S.K. and Naga Prasad, S.V. (2011). Regulation of b- Adrenergic receptor function: An emphasis on receptor resensitization. Cell Cycle, 10 (21): 3684-3691.
- Vasudevan, N.T., Mohan, M.L., Gupta, M.K., Hussain, A. and Naga Prasad, S.V. (2011). Inhibition of protein phosphatase 2A activity by PI3Kg regulates beta-adrenergic receptor function. Mol. Cell, 41 (6): 636-648.
A complete list of Dr. Prasad's publications may be viewed at PubMed.