Adenosine is a nucleoside that influences the activity of numerous tissues by binding to specific cell surface receptors. Growing evidence suggests that A1 adenosine receptors (A1ARs) are important neuromodulators that are widely distributed in the mammalian brain. A1ARs are believed to tonically inhibit neural activity, and activation of A1ARs can stop seizures. A1ARs may modulate the action of excitatory neurotransmitters, and A1AR activation also may help protect the brain against injury. Increasing evidence suggests that the hippocampal formation is an important site of A1AR action. In comparison with what is known about other receptor systems in the brain, surprisingly little is known about the neural adenosinergic system. Using contemporary molecular and biochemical techniques, we propose to examine the sites and mechanisms of A1AR action in the hippocampus. First, we will identify the cellular sites of A1ARs in human hippocampus. We will use immunohistochemistry, receptor autoradiography and in situ hybridization for these studies. Second, we will examine the structural basis of how the human A1AR interacts with agonists and antagonist. Using chimeric receptors, we will identify transmembrane domains of that are important for ligand binding. We will then use small chimeric constructs and site-directed mutagenesis to localize specific amino acids that are important for binding agonists, antagonists, and adenosine enhancers. Third, we will examine if A1AR activation alone influences hippocampal physiology, and examine if adenosine itself acts predominantly via A1ARs. Using rat hippocampal slices, we will examine if A1ARs inhibit excitatory amino acid release and examine if A1ARs influence hippocampal gene expression. A1ARs may play a very important role in the pathogenesis and treatment of nervous system disorders including epilepsy. Understanding the basic mechanisms of human A1AR action in hippocampus, will allow us to better understand the role of this important receptor system in human neural physiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033539-04
Application #
2685707
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Jacobs, Margaret
Project Start
1996-05-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
2000-03-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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