The physiological responses of many hormones, neurotransmitters, growth factors, and other extracellular stimuli are mediated through phospholipase C (PLC)-catalyzed hydrolysis of membrane phosphoinositides. A long-term goal of our research is to delineate the molecular mechanisms whereby PLC activity is modulated by receptor-activated heterotrimeric and Ras superfamily G proteins, as well as by other regulators. This work currently focuses on three PLC isozymes: (1) PLC-β isozymes, which are the prototypical heterotrimeric G protein-regulated PLCs, (2) PLC-ε, which we discovered is uniquely directly activated by both Rho and Ras GTPases acting through independent domains; and (3) PLC-η2, which we recently cloned and illustrated is a direct effector of Gβγ. These studies are carried out in close collaboration with John Sondek and are increasingly driven by high-resolution crystal structures.
Our research also focuses on mechanistic and pharmacological aspects of a class of G protein-coupled receptors (the eight member P2Y receptor family) for extracellular nucleotides. Clopidogrel (Plavix), an important and highly prescribed antithrombotic agent, targets the P2Y12 receptor, and the potential for therapeutic intervention at this and the other seven P2Y receptors is very high. Therefore, one of the goals of our P2Y receptor research program is to develop highly selective agonists and antagonists of each of the P2Y receptor subtypes. This work is carried out in close collaboration with Ken Jacobson at the National Institute of Health.
Recent Publications:
Seifert, J.P., Zhou, Y., Hicks, S.N., Sondek, J., and Harden, T.K. (2008) Dual activation of phospholipase C-ε by Rho and Ras GTPases. J Biol Chem [Epub ahead of print] Abstract
Hicks, S.N., Jezyk, M., Seifert, J.P., Harden, T.K., and Sondek, J. (2008) General and versatile autoinhibition of phospholipase C isozymes. Mol Cell 31: 383-394. Abstract
Fricks, I.P., Maddileti, S., Lazarowski, E.R., Nicholas, R.A., Jacobson, K.A., and Harden, T.K. (2008) UDP is a competitive antagonist at the human P2Y14 receptor. J Pharmacol Exp Ther 325: 588-594. Abstract
Zhou, Y., Sondek, J., and Harden, T.K. (2008) Activation of human phospholipase C-η2 by Gβγ. Biochemistry 47: 4410-4417. Abstract
Cheever, M.L., Snyder, J.T., Gershburg, S., Siderovski, D.P., Harden, T.K., and Sondek, J. (2008) Crystal structure of the multifunctional Gβ5-RGS9 complex. Nature Struct Mol Biol 15: 155-162. Abstract
