Our long term goals are to study transmembrane signalling by heterotrimeric G proteins. The structure and most molecular aspects of transmembrane signalling G proteins have been solved, but their respective participation in complex homeostatic processes such as inflammatory reactions, pain perception, behavior and maintenance of normal glycemia remains largely unknown. During the previous and this last granting period we began addressing the roles of G proteins in homeostasis by creating mice lacking specific G proteins (knockout mice). We have now individually knocked out four of the 15 G protein alpha subunit genes: Gi1, Gi2, Gi3 and Go, and we also have a double and Gi1/Gi3 knockout. These G proteins form the group of non-sensory pertussis toxin (PTX)-sensitive G proteins which couples a distinct set of receptors to a common set of effectors. Two of the knockouts (Gi1 and Gi3, and their combination) are so far asymptomatic. Gi2-/- mice develop ulcerative colitis (UC) and adeno-carcinomas, but in a context sensitive manner, i.e., depending on the strain (genomic background). Go-/-mice have multiple neurological alterations and term this phenotype 'rotator'. Go-/- mice also show unexpected alterations in Ca2+ channel function and, when subjected to a glucose load, respond with a much tighter control of glycemia than controls. For the coming years we propose: a. To complete the disruption of the Gz G protein, which shares with the inactivated G protein alpha subunits a high degree of structural and functional similarity, coupling the same set of receptors to the same set of effectors, but is PTX- insensitive. This will be complemented by the creation by breeding of the compound G protein deficiencies. b. To search for and characterize one or more genes responsible for suppression (or promotion) of the development of UC and adenocarcinomas in Gi2-/- mice. c. To search for the neurotransmitter system(s) in the CNS affected by lack of Go and, if possible, interpret the rotator phenotype in terms of existing theories of central nervous system motor circuits. And d. to characterize insulin secreting properties of Go-/- islets in vivo and in vitro. The identification of one or more modifier genes of UC and/or adenocarcinoma formation may aid in the elucidation of the etiology of human UC and its complications (adenocarcinomas). Investigation of the role of Gz is expected to shed new light on molecular mechanisms involved in thrombus formation. The elucidation of the mechanism(s) altered by lack of Go may aid in the understanding of human motor disorders and may shed new light on development and/or treatment of type II diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Abraham, Kristin M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Tang, Guanghua; Wang, Ying; Park, Sangeun et al. (2012) Go2 G protein mediates galanin inhibitory effects on insulin release from pancreatic ? cells. Proc Natl Acad Sci U S A 109:2636-41
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
Fan, Hongkuan; Williams, David L; Zingarelli, Basilia et al. (2007) Differential regulation of lipopolysaccharide and Gram-positive bacteria induced cytokine and chemokine production in macrophages by Galpha(i) proteins. Immunology 122:116-23
Gohla, Antje; Klement, Karinna; Piekorz, Roland P et al. (2007) An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver. Proc Natl Acad Sci U S A 104:3003-8
Fan, Hongkuan; Williams, David L; Zingarelli, Basilia et al. (2006) Differential regulation of lipopolysaccharide and Gram-positive bacteria induced cytokine and chemokine production in splenocytes by Galphai proteins. Biochim Biophys Acta 1763:1051-8
Wei, Bo; Velazquez, Peter; Turovskaya, Olga et al. (2005) Mesenteric B cells centrally inhibit CD4+ T cell colitis through interaction with regulatory T cell subsets. Proc Natl Acad Sci U S A 102:2010-5
Pineda, Victor V; Athos, Jaime I; Wang, Hongbing et al. (2004) Removal of G(ialpha1) constraints on adenylyl cyclase in the hippocampus enhances LTP and impairs memory formation. Neuron 41:153-63
Foerster, Katharina; Groner, Ferdi; Matthes, Jan et al. (2003) Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through beta 2-adrenoceptors. Proc Natl Acad Sci U S A 100:14475-80
Dhingra, Anuradha; Jiang, Meisheng; Wang, Tian-Li et al. (2002) Light response of retinal ON bipolar cells requires a specific splice variant of Galpha(o). J Neurosci 22:4878-84
Jiang, M; Spicher, K; Boulay, G et al. (2001) Most central nervous system D2 dopamine receptors are coupled to their effectors by Go. Proc Natl Acad Sci U S A 98:3577-82

Showing the most recent 10 out of 73 publications