The present studies are aimed at examining, using a molecular biological approach, the structural basis for the diverse functional properties of alpha2-adrenergic receptors. We plan to clone the porcine gene that codes for the alpha2-adrenergic receptor that we have purified to homogeneity. We will exploit insights gained from domain mapping and biochemical analysis of the purified receptor to delineate those areas of the receptor that we can analyze further by deletion and site-directed mutagenesis to learn what structural components are involved in ligand recognition, allosteric effects on adrenergic binding by Na+, H+ and 5-amino-substituted analogs of amiloride, receptor-GTP binding protein interactions, receptor-accelerated Na+/H+ exchange and receptor mediated inhibition of adenylate cyclase. Furthermore, we plan to examine what role different functional domains of the receptor play in the overall physiological functions influenced by alpha2-adrenergic receptors, such as suppression of neurotransmitter release, by expressing mutated versus wild type receptors in appropriate target cells to determine what effect discrete deletion or site mutations have on particular alpha2-receptor functions. We anticipate that the proposed studies will provide new insights into the structural basis for many of the functional properties of alpha2-receptors and perhaps suggest novel loci for drug development in mimicking, or blocking, the effects of alpha2-adrenergic agents in particular physiological processes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37HL043671-06
Application #
2221123
Study Section
Special Emphasis Panel (NSS)
Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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