In embryonic chick dorsal root ganglion neurons, neuronal calcium current is inhibited by norepinephrine (NE) via activation of alpha2- adrenergic receptors. The NE-mediated inhibition has two components, a voltage-dependent slowing of the activation kinetics (KS) and a voltage-independent steady-state inhibition (SSI). NE-mediated KS requires the activation of Go, and G alphao is the functional subunit. Steady-state inhibition requires the activation of Gi and protein kinase C, and Gbetagamma is the functional subunit. Preliminary results show that the onset of desensitization of both modulatory components require receptor-mediated G protein activation. My previous results demonstrated that a G protein-coupled receptor kinase GRK3 plays a central role in desensitizing both pathways. Recent experiments presented in this application have shown that RGS proteins, which are known to accelerate the rate of GTPase activity, selectively alter the time course of desensitization of the two signaling pathways. The experiments proposed in this application will use a combination of electrophysiological and molecular biological techniques to explore the molecular loci that specify the G protein subtype-specific rates of desensitization. The working hypothesis for these experiments is that differences in the functional domains of RGS proteins and in the regulation of GTPase activity of and alphai and alphao by RGS proteins, give rise to the G protein subtype-specific time course of desensitization. Understanding these mechanisms will pave the way for the development of new drugs useful in the treatment of disorders associated with elevated NE levels. Such an approach will also have general applicability for other disorders, such as stroke, or clinical problems, such as drug tolerance, that are associated with unnaturally high extracellular hormone or drug concentrations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037443-02
Application #
6126322
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Michel, Mary E
Project Start
1998-12-03
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
2
Fiscal Year
2000
Total Cost
$232,292
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
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