The G protein signal transduction system represents a source of important specific targets for a variety of therapeutic approaches ranging from the control of blood pressure, allergic response, kidney function, hormonal disorders to neurological disease and pain. It has been estimated that 30-40% of the pharmaceutical products sold in the United States target G protein mediated signal transduction system. We are analyzing the interactions in this complex information processing system at the level of purified proteins, the cellular level and the whole animal level. If we can connect the biochemical changes that are the result of specific protein modifications to the effects of those mutations on cellular function and eventually the effects of cellular function on complex physiology or changes in development and differentiation, we will have gone a long way toward an integral understanding of these systems. In the next grant period we intend to pursue these molecular biochemical and genetic approaches. We will analyze transgenic mice that we have constructed together with our collaborators that result in the disruption or deletion of all of the G/alpha subunits in the Gq signaling pathway as well as mice that we have constructed that have the G/alpha13 and G/alpha12 genes disrupted and animals with deletions of the PI-PLC beta2 and PI-PLC beta4 genes. We will try to determine the specific effects of these mutations on cell and tissue function. We will also examine the effects of mutants in tissue culture and delineate the functions of individual G protein pathways. We will study the modifications of the different components of the G proteins that result from the activation of specific signaling pathways and understand how these modifications affect and integrate different signal transducing pathways. Finally, we will continue our studies on the molecular modification of individual G protein components and measure the effect of modification on protein- protein interaction using plasmon resonance and a variety of other techniques to develop a quantitative picture of the elements necessary for the interaction of components in a specific pathway. These studies will provide a deeper insight into the function of two less well studied G protein families, the Gq and the G12 families. We hope eventually to be able to develop models of how specific signal transductions pathways process information and how these pathways interact and we expect that such models will be important in predicting and developing new approaches to ameliorating the effects of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37GM034236-13
Application #
2657226
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1988-04-01
Project End
2002-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
13
Fiscal Year
1997
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Pero, Ralph S; Borchers, Michael T; Spicher, Karsten et al. (2007) Galphai2-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation. Proc Natl Acad Sci U S A 104:4371-6
Shin, Kum-Joo; Wall, Estelle A; Zavzavadjian, Joelle R et al. (2006) A single lentiviral vector platform for microRNA-based conditional RNA interference and coordinated transgene expression. Proc Natl Acad Sci U S A 103:13759-64
Hwang, Jong-Ik; Choi, Sangdun; Fraser, Iain D C et al. (2005) Silencing the expression of multiple Gbeta-subunits eliminates signaling mediated by all four families of G proteins. Proc Natl Acad Sci U S A 102:9493-8
Hwang, Jong-Ik; Fraser, Iain D C; Choi, Sangdun et al. (2004) Analysis of C5a-mediated chemotaxis by lentiviral delivery of small interfering RNA. Proc Natl Acad Sci U S A 101:488-93
Slice, Lee W; Han, Sang-Kyou; Simon, Melvin I (2003) Galphaq signaling is required for Rho-dependent transcriptional activation of the cyclooxygenase-2 promoter in fibroblasts. J Cell Physiol 194:127-38
Bastiani, Carol A; Gharib, Shahla; Simon, Melvin I et al. (2003) Caenorhabditis elegans Galphaq regulates egg-laying behavior via a PLCbeta-independent and serotonin-dependent signaling pathway and likely functions both in the nervous system and in muscle. Genetics 165:1805-22
Han, Sang-Kyou; Dong, Xinzhong; Hwang, Jong-Ik et al. (2002) Orphan G protein-coupled receptors MrgA1 and MrgC11 are distinctively activated by RF-amide-related peptides through the Galpha q/11 pathway. Proc Natl Acad Sci U S A 99:14740-5
Dong, X; Han, S; Zylka, M J et al. (2001) A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106:619-32
Offermanns, S; Negulescu, P; Hu, Y H et al. (2001) Conditionally expressed G alpha 15 couples to endogenous receptors in GH3 cells. Naunyn Schmiedebergs Arch Pharmacol 364:140-8
Kabarowski, J H; Feramisco, J D; Le, L Q et al. (2000) Direct genetic demonstration of G alpha 13 coupling to the orphan G protein-coupled receptor G2A leading to RhoA-dependent actin rearrangement. Proc Natl Acad Sci U S A 97:12109-14

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