Regulation of Adenylyl Cyclase
The enzyme adenylyl cyclase synthesizes the intracellular second messenger cyclic AMP, which plays a key role in functions ranging from control of heart rate and force of contraction to learning and memory. Many hormones and drugs mediate their actions by binding to G protein-coupled receptors that regulate cAMP production. Our laboratory is using structural, biochemical, live-cell imaging, and molecular biology techniques to understand the complex regulation of adenylyl cyclase by heterotrimeric GTP-binding proteins and regulators of G protein signaling (RGS proteins).
A major question in the laboratory is how the fidelity of signaling is maintained within a cell. Cyclic AMP is a small diffusible molecule, yet many hormones stimulate cAMP production but elicit different biological responses. We are examining how localization of adenylyl cyclase to specific complexes within the membrane plays a role in cellular signaling. We have discovered that specific anchoring proteins of cAMP-dependent kinase (AKAPs) recruit adenylyl cyclase as well as other regulatory molecules. These signaling complexes have important roles at post-synaptic densities in the brain to control glutamate signaling and also function in the heart to control contractile events. We are currently using biochemical and functional studies in brain and heart to further define the nature of adenylyl cyclase complexes and to understand how specificity of signaling is generated and maintained.
The structure of the cytoplasmic domains of adenylyl cyclase bound to forskolin is shown (C1 domain in gold; C2 domain in purple). The movement of these domains upon binding substrate is highlighted in a and b. Those regions that undergo the most movement are colored in red. Regulators of the enzyme will ultimately control the dynamics of these domains.
Kapiloff MS, Piggott LA, Sadana R, Li J, Heredia LA, Henson E, Efendiev R, Dessauer CW. An adenylyl cyclase-mAKAP{beta} signaling complex regulates cAMP levels in cardiac myocytes. J Biol Chem. 2009 Jul 1. [Epub ahead of print]
Sadana R, Dessauer CW. Physiological roles for G protein-regulated adenylyl cyclase isoforms: insights from knockout and overexpression studies. Neurosignals. 17:5-22, 2009.
Piggott LA, Bauman AL, Scott JD, Dessauer CW. The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain. Proc Natl Acad Sci U S A. 105:13835-13840, 2008.
Gu S, Anton A, Salim S, Blumer KJ, Dessauer CW, Heximer SP. Alternative translation initiation of human regulators of G-protein signaling-2 yields a set of functionally distinct proteins. Mol Pharmacol. 73:1-11, 2008.
Gao, X., Sadana, R., Dessauer, C.W., and Patel, T.B. Conditional Stimulation of Type V and VI Adenylyl Cyclase by G protein bg Subunits. J. Biol. Chem., 282: 294-302, 2007
Bauman, A., Soughayer, J., Nguyen, B.T., Willoughby, D., Wong, W., Hoshi, N., Langeberg, L.K., Cooper, D.M.F., Dessauer, C.W., and Scott, J.D. Dynamic regulation of cAMP synthesis through anchored PKA/Adenylyl cyclase V/VI complexes. Molecular Cell, 23:925-931, 2006.
Nguyen, B.T. and Dessauer, C.W. Relaxin Stimulates PKCz Translocation via PI3K to Increase cAMP Production in THP-1 Cells. Mol. Endo., 19:1012-1023, 2005.
Chen-Goodspeed, M., Lukan, A.N., and Dessauer, C.W. Modeling of Gai and Gas Regulation by Human Types V and VI Adenylyl Cyclase. J. Biol. Chem., 280:1808-1816, 2005.
Salim, S., Sinnarajah, S., Kehrl, J.H., and Dessauer, C.W. Identification of RGS2 and Type V Adenylyl Cyclase Interaction Sites. J. Biol. Chem. 278:15842-15849, 2003.
Sinnarajah, S., Dessauer, C.W., Srikumar, D., Chen, J., Yuen, J., Yilman, S., Dennis, J.C. Morrison, E.E., Vodyanoy, V., and Kehrl, J.H. RGS2 Regulates Signal Transduction in Olfactory Neurons by Attenuating Adenylyl Cyclase III Activation. Nature 409:1051-1055, 2001.
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Department of Integrative Biology and Pharmacology