Alcohol and inhibitory receptors: unexpected specificity from a nonspecific drug
| Autor: | R. A. Harris, S. J. Mihic |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Drug
endocrine system media_common.quotation_subject Membrane lipids Drug Resistance Alcohol Pharmacology chemistry.chemical_compound Mice Species Specificity mental disorders medicine Animals Humans Receptor reproductive and urinary physiology media_common Mice Knockout Multidisciplinary Ethanol GABAA receptor Biological Sciences Receptors GABA-A Electrophysiology Protein Subunits Mechanism of action chemistry medicine.symptom |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 101(1) |
| ISSN: | 0027-8424 |
| Popis: | It is remarkable that a simple two-carbon molecule like ethyl alcohol produces the many neurological, physiological, and societal effects that result from alcohol (ethanol) use and misuse. It is the least potent of all drugs, requiring concentrations of 10-20 mM to produce intoxication in humans and 100-200 mM to produce anesthesia in experimental animals (1, 2). Because of the limited structural information that can be obtained from such a simple molecule and the high concentrations required, a nonspecific or nonreceptor-mediated mechanism of action was considered likely, and, as a result, early studies focused on the actions of alcohol on physical properties of membrane lipids. More recently, the search for sites of action shifted from lipids to proteins, but the identification of brain proteins that are clearly affected by ethanol at concentrations of 10-20 mM has proven remarkably elusive. For reference, a moderately intoxicating blood alcohol level of 0.08% (80 mg/dl) is equivalent to an ethanol concentration of 17 mM. In 1986 an important first step toward defining targets of alcohol action was taken when three groups demonstrated that intoxicating concentrations of ethanol enhance the function of γ-aminobutyric acid type A (GABAA) receptors, the major inhibitory neurotransmitter receptors in the brain (3-5). One of these studies also showed that this action was missing in a line of mice (short-sleep mice) exhibiting genetic resistance to alcohol actions, suggesting the existence of alcohol-sensitive and alcohol-resistant subtypes of GABAA receptors (3). Despite the numerous electrophysiological studies stimulated by these studies, there is no clear understanding of what makes a GABAA receptor sensitive to low millimolar concentrations of ethanol and indeed many studies find either no effect of ethanol or effects only at concentrations of ≈100 mM or more (6). |
| Databáze: | OpenAIRE |
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