The molecular etiology of the cardiomyopathy associated with chronic alcohol consumption is not established. Among its many acute actions, ethanol has been shown to inhibit cardiac L-type ca2+ channels. Because L- type ca2+ channels play a crucial role in excitation-contraction coupling in the heart, it has been proposed that the direct inhibition of these channels by ethanol contributes to chronic alcoholic cardiomyopathy. Ethanol may also have indirect effects on ca2+ channel activity through the ability to modulate the beta-adrenergic stimulation or dihydropyridine inhibition of these channels. Thus, the proposed studies will examine both direct and indirect mechanisms for ethanol action. The long-term goals of this proposal are; 1) to understand, at the molecular level, how ethanol inhibits cardiac L-type Ca2+ channels, and 2) to establish how hormonal stimulation (epinephrine) and antiarrhythmic drugs (e.g. dyhydropyridines) may modulate such inhibition. This project will apply complementary DNA, molecular biological, biochemical and cellular electrophysiological methodologies to examine the following specific aims: 1) to characterize the molecular determinants that contribute to the ethanol inhibition of recombinant L-type Ca2+ channels; 2) to characterize the biophysical effects of ethanol on recombinant L-type Ca2+ channels; and 3) to investigate the modulatory effects of intrinsic factors on the inhibition of recombinant L-type Ca2+ channels by ethanoL. Although these aims are focused on cardiac L-type ca2+ channels, similar channels are also present in other excitable tissues, such as the nervous system. In some of the proposed experiments, brain isoforms of the L-type ca2+ channel, as well as additional neuronal voltage-gated ca2+ channels, will be studied. Thus, the results obtained from this component of the Alcohol Research Center should also be relevant to our understanding of ethanol action in both the heart and the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA007186-15
Application #
6200873
Study Section
Project Start
1999-12-01
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
15
Fiscal Year
2000
Total Cost
$130,719
Indirect Cost
Name
Thomas Jefferson University
Department
Type
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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