Abstract

The long range goals of this project is to contribute to our understanding of the causes and control of diabetes mellitus. The immediate goals are to develop and improve the methods for the chemical synthesis of pure glucagon and its analogs and then to design and synthesize peptides that will be effective inhibitors of the hormone. Such inhibitors ar expected to aid in studies on the mechanism of action of glucagon and to provide an agent for the in vivo regulation of glucagon activity and of blood glucose concentration. The syntheses will be based on the solid phase method, and several recently developed improvements will be incorporated into the proposed new syntheses. The design of the analogs will be based on conformation predictions, X-ray data, NMR and circular dichroism data in dilute solution, and correlations of existing membrane binding and adenyl cyclase activation data.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK024039-11
Application #
3227265
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1978-09-15
Project End
1990-08-31
Budget Start
1988-09-01
Budget End
1989-08-31
Support Year
11
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Rockefeller University
Department
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

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

Showing the most recent 10 out of 18 publications