During the past funding period, we have discovered a number of details of the mechanisms underlying acute ethanol inhibition of voltage-gated calcium channels (VGCC)in PC12 cells, including the involvement of identified G-proteins. We have also discovered that differentiation with nerve growth factor (NGF), as well as chronic exposure to ethanol, significantly decreases acute ethanol inhibition. We plan to focus the next phase of our research on the mechanisms underlying the inhibition of Ga channels. This work, which will use a combination of molecular biology and biophysics, will be performed on three types of preparation, each contributing particular advantages: 1) intact PG12 cells, where we will further elucidate the mechanisms of ethanol action on VGCC; 2) the intact oocyte expression system, where we can study selected populations of channels and components, such as G-proteins, in a cellular environment; and 3)internally perfused oocytes, in which we can manipulate both the interior and exterior environment, maintaining a natural membrane and underlying cytoskeleton. At each level, we will study channels from undifferentiated cells, differentiated cells, and cells chronically exposed to alcohol, allowing us to gain an understanding for the basis of differences in acute sensitivity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA005542-16
Application #
2893988
Study Section
Special Emphasis Panel (SRCA (58))
Project Start
1991-08-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
16
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pharmacology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Levine, John B; Martin, Gilles; Wilson, Andrew et al. (2003) Clozapine inhibits isolated N-methyl-D-aspartate receptors expressed in xenopus oocytes in a subunit specific manner. Neurosci Lett 346:125-8