The long range goal of this project is to contribute to our understanding of the role of the hormone glucagon in diabetes mellitus and in intracellular signaling in general. Our immediate goals are to design and synthesize peptide analogs that will be potent antagonists of the hormone, using as our principal tool, solid phase peptide synthesis. Our work will be guided by conformation predictions, X-ray data, NMR, and circular dichroism and their correlations with biological assay data. Such inhibitors are expected to aid in the studies of the mechanism of action of glucagon at the receptor level, and to provide a potentially therapeutic agent for in vivo regulation of blood glucose in the management of diabetes. We are extending the scope of our studies into the isolation of the glucagon receptor itself, and into post-receptor interactions that involve the regulatory guanine-nucleotide binding proteins. Purification and characterization of the receptor will be an invaluable tool in the study of hormone/receptor/G-protein/ effector interaction and will lead to an understanding of peptide hormone signal transduction and the control of diseases like diabetes mellitus.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Physiological Chemistry Study Section (PC)
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Rockefeller University
Other Domestic Higher Education
New York
United States
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Sachdev, Pallavi; Tirunagari, Laxmi Manohar; Kappei, Dennis et al. (2009) Monitoring glucagon and glucagon antagonist-mediated internalization: a useful approach to study glucagon receptor pharmacology. Adv Exp Med Biol 611:325-6
Unson, Cecilia G (2008) Expression of glucagon receptors in tetracycline-inducible HEK293S GnT1- stable cell lines: an approach toward purification of receptor protein for structural studies. Biopolymers 90:287-96
Sapse, Anne-Marie; Rothchild, Robert; Jain, Duli C et al. (2002) The role of salt bridge formation in glucagon: an experimental and theoretical study of glucagon analogs and peptide fragments of glucagon. Mol Med 8:251-62
Unson, Cecilia G; Wu, Cui-Rong; Jiang, Youwei et al. (2002) Roles of specific extracellular domains of the glucagon receptor in ligand binding and signaling. Biochemistry 41:11795-803
Jiang, Y; Cypess, A M; Muse, E D et al. (2001) Glucagon receptor activates extracellular signal-regulated protein kinase 1/2 via cAMP-dependent protein kinase. Proc Natl Acad Sci U S A 98:10102-7
Unson, C G; Wu, C R; Sakmar, T P et al. (2000) Selective stabilization of the high affinity binding conformation of glucagon receptor by the long splice variant of Galpha(s). J Biol Chem 275:21631-8
Cypess, A M; Unson, C G; Wu, C R et al. (1999) Two cytoplasmic loops of the glucagon receptor are required to elevate cAMP or intracellular calcium. J Biol Chem 274:19455-64
Unson, C G; Wu, C R; Cheung, C P et al. (1998) Positively charged residues at positions 12, 17, and 18 of glucagon ensure maximum biological potency. J Biol Chem 273:10308-12
Unson, C G; Cypess, A M; Wu, C R et al. (1996) Antibodies against specific extracellular epitopes of the glucagon receptor block glucagon binding. Proc Natl Acad Sci U S A 93:310-5
Unson, C G; Cypess, A M; Kim, H N et al. (1995) Characterization of deletion and truncation mutants of the rat glucagon receptor. Seven transmembrane segments are necessary for receptor transport to the plasma membrane and glucagon binding. J Biol Chem 270:27720-7

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