My research is focused on understanding the regulation of adenylyl cyclase (AC) VII and its physiological functions. Mammalian cells have nine membrane-bound ACs, which catalyze the conversion of ATP to cAMP upon activation by the Gs protein. cAMP is a ubiquitous second messenger that mediates a wide range of cellular functions including cell metabolism, cell proliferation and differentiation, immune responses, memory formation, and cardiac contractility. Therefore regulation of cAMP synthesis has important physiological relevance. Each of the AC isoforms is distinctively regulated by a variety of pathways including Gi, Gbg, Ca2+, and protein kinase C. Recently, in collaboration with Dr. Paul Sternweis, we identified a novel pathway that regulates cAMP responses in several immune cells including the bone marrow derived primary macrophages. In these cells, activation of the G13 pathway by distinct G protein coupled receptors synergistically enhances Gs-activated cAMP synthesis. This synergistic interaction converges on a specific isoform of adenylyl cyclase (AC), AC VII. This is the first demonstration that the G12/G13 subclass of G proteins can regulate cAMP responses and of a specific function for AC7. Current research is aimed at dissecting the molecular mechanisms of the interactions between the G12/13 pathway and AC7 using a variety of biochemical approaches, including protein-protein interactions, gene knockdown by RNAi, and identification of novel proteins involved in this interaction.
Deficiency of AC7 in the immune system results in compromised immune responses, suggesting an important role of this AC isoform in the immune functions. In collaboration with Dr. Dorothy Yuan, we are further characterizing these defects to define defective cell types and signaling pathways.
In addition to the defects in the immune system, AC7 deficient mice also show defects in placenta development and in hormone metabolism. These will be further studied with the use of a conditional knockout strain.
RESEARCH INTERESTS
cAMP regulation in the immune system
Molecular mechanisms of adenylyl cyclase VII regulation
Physiological functions of AC VII
Develop biosensors to monitor intracellular signaling transductions
RECENT PUBLICATIONS
Jiang, L.I., Collins, J., Davis, R., Lin, K.M., DeCamp, D., Roach, T., Hsueh, R., Rebres, R.A., Ross, E.M., Taussig, R., Fraser, I., Sternweis, P.C., "Use of a cAMP BRET sensor to characterize a novel regulation of cAMP by the sphingosine 1-phosphate/G13 pathway." J Biol Chem., 282(14):10576-84, April 2007
Jiang, L.I., Collins, J., Davis, R., Fraser, I.D., Sternweis, P.C., "Regulation of cAMP responses by the G12/13 pathway converges on adenylyl cyclase VII." J Biol Chem., 283(34):23429-39, August 2008
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