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Ethanol enhances agonist-induced fast desensitization in nicotinic acetylcholine receptors.

Abstract：

:The reversible decline of the nicotinic acetylcholine receptor's response to acetylcholine during prolonged exposure to acetylcholine is known as desensitization. Here, we studied ethanol's modulation of fast agonist-induced desensitization of the nicotinic acetylcholine receptor in postsynaptic membrane vesicles from Torpedo using a fast kinetic technique: pulsed quenched flow. Preincubation of the vesicles with various concentrations of acetylcholine at 4 degrees C for times ranging from 80 ms to 1.5 s caused fast desensitization, which was revealed as a decreased 86Rb+ influx when the vesicles were subsequently briefly exposed to a saturating concentration of acetylcholine in 86RbCl. Acetylcholine-induced fast desensitization had a maximum observed rate, kdmax, of 6.8 s-1, a half-effect concentration, KD, of 157 microM, and a Hill coefficient of 1.4. Increasing the ethanol concentration up to 1.0 M causes a linear increase in kdmax, such that 1.0 M ethanol doubles the rate. Ethanol (1 M) also decreased KD 10-fold without changing the Hill coefficient. We consider a modified sequential model to interpret our data. Two acetylcholine molecules bind sequentially to the receptor's resting state to form a pre-open (closed) state, which then opens and, at very high acetylcholine concentrations, is inhibited. A priori fast desensitization might occur from any of these acetylcholine-occupied states. If we assume fast desensitization to occur solely from the pre-open state, our data predict an excessively large action of ethanol on the fast desensitization rate constant (> 200-fold increase in the desensitization rate constant at 1 M ethanol). When we assume fast desensitization to occur from all states, ethanol is seen to have two actions.(ABSTRACT TRUNCATED AT 250 WORDS)

journal_name

Biochemistry

journal_title

Biochemistry

authors

Wu G,Miller KW

doi

10.1021/bi00197a009

subject

Has Abstract

pub_date

1994-08-09 00:00:00

pages

9085-91

issue

31

eissn

0006-2960

issn

1520-4995

journal_volume

33

pub_type

杂志文章

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