Improved kinetic models to describe the activation of adenylyl cyclase by beta-adrenergic receptors (BAR) have been developed. The utility of those models has been demonstrated using cultured murine lymphoma cells (S49). Using these models the interaction time between BAR and the guanine nucleotide binding protein (G) in these cells has been estimated at about one second and the number of receptors encountering each cyclase moiety per minute is around 100. Information of this type has not been available previously. At the same time, the importance of these basic kinetic data to adenylyl cyclase activation by agonist and its inhibition by antagonists has been demonstrated. A separate model has allowed the determination by antagonists has been demonstrated. A separate model has allow the determination of a quantitative relationship between hormone efficiency and the energetics of the rate limiting step for adenylyl cyclase activation has been possible. These approaches will be extended to partially purified systems. Some aspects of the models will be independently confirmed using transection techniques to modify the expression of G. The G-proteins constitute and important class of proteins of which G, is only one of many members. They are distributed in all tissues and seen to be universal in multicellular organisms. The BAR/G/adenylyl cyclase system is the best described and understood of these receptor/G- protein/effector processes. It is to be expected that a knowledge of the mechanisms of adenylyl cyclase activation will have wide applicability in understanding the control of G-protein activity in general. Methodology includes: a) ligand binding kinetics, b) mathematical modelling, c) enzymology with adenylyl cyclase, and d) recombinant DNA technology. It is expected that a quantitative knowledge of adenylyl cyclase activation should lead to a better understanding of desensitization (tolerance) and to improved drug design for the clinically important B-adrenergic antagonists.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Project (R01)
Project #
5R01RR007710-02
Application #
2283564
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1994-05-01
Project End
1997-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225