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| A DISCRETE SITE FOR GENERAL-ANESTHETICS ON A POSTSYNAPTIC RECEPTOR |
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| Author(s): FORMAN SA, MILLER KW, YELLEN G |
| Source: MOLECULAR PHARMACOLOGY Volume: 48 Issue: 4 Pages: 574-581 Published: OCT 1995 |
| Times Cited: 127 References: 28 |
| Abstract: General anesthetics depress central nervous system excitability via a mechanism that probably involves effects on synaptic ion channels, but the fundamental molecular nature of the site where they act is unknown. Although the importance of hydrophobicity for general anesthetic drug potency has long been established, it remains uncertain whether these ''nonspecific'' drugs act on membrane proteins directly or by modification of the physical properties of the lipid membrane or the lipid-protein interface. We find that specific mutations in the acetylcholine receptor pore-forming M2 domains enhance the sensitivity of the receptor to the general anesthetics isoflurane, hexanol, and octanol, suggesting that these agents act by binding directly to a discrete protein site at or near these residues. The sensitivity of the receptor to block by general anesthetics increases with increased hydrophobicity of these residues, demonstrating that hydrophobic forces dominate the interaction of drugs with their protein site. Furthermore, octanol inhibits both wild-type and mutant nicotinic acetylcholine receptors preferentially after channel opening, which is consistent with a mechanism where drugs bind within the receptor's pore. Similar sites on postsynaptic ion channels in brain may represent general anesthetic targets for modulating consciousness. |
| Document Type: Article |
| Language: English |
Addresses:
1. MASSACHUSETTS GEN HOSP, BOSTON, MA 02114 USA
2. HARVARD UNIV, SCH MED, DEPT ANESTHESIA, BOSTON, MA 02114 USA
3. HARVARD UNIV, SCH MED, DEPT BIOL CHEM & MOLEC PHARMACOL, BOSTON, MA 02114 USA
4. HARVARD UNIV, SCH MED, DEPT NEUROBIOL, BOSTON, MA 02114 USA |
| Publisher: WILLIAMS & WILKINS, 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 |
| Subject Category: Pharmacology & Pharmacy |
| IDS Number: TA567 |
| ISSN: 0026-895X |
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