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Antagonist activities of mecamylamine and nicotine show reciprocal dependence on beta subunit sequence in the second transmembrane domain.
Webster JC
,
Francis MM
,
Porter JK
,
Robinson G
,
Stokes C
,
Horenstein B
,
Papke RL
.
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We show that a portion of the TM2 domain regulates the sensitivity of beta subunit-containing rat neuronal nicotinic AChR to the ganglionic blocker mecamylamine, such that the substitution of 4 amino acids of the muscle beta subunit sequence into the neuronal beta4 sequence decreases the potency of mecamylamine by a factor of 200 and eliminates any long-term effects of this drug on receptor function. The same exchange of sequence that decreases inhibition by mecamylamine produces a comparable potentiation of long-term inhibition by nicotine. Inhibition by mecamylamine is voltage-dependent, suggesting a direct interaction of mecamylamine with sequence elements within the membrane field. We have previously shown that sensitivity to TMP (tetramethylpiperidine) inhibitors is controlled by the same sequence elements that determine mecamylamine sensitivity. However, inhibition by bis-TMP compounds is independent of voltage. Our experiments did not show any influence of voltage on the inhibition of chimeric receptors by nicotine, suggesting that the inhibitory effects of nicotine are mediated by binding to a site outside the membrane's electric field. An analysis of point mutations indicates that the residues at the 6' position within the beta subunit TM2 domain may be important for determining the effects of both mecamylamine and nicotine in a reciprocal manner. Single mutations at the 10' position are not sufficient to produce effects, but 6' 10' double mutants show more effect than do the 6' single mutants.
Ascher,
Studies on the mechanism of action of acetylcholine antagonists on rat parasympathetic ganglion cells.
1979, Pubmed
Ascher,
Studies on the mechanism of action of acetylcholine antagonists on rat parasympathetic ganglion cells.
1979,
Pubmed
Bertrand,
Activation and blocking of neuronal nicotinic acetylcholine receptor reconstituted in Xenopus oocytes.
1990,
Pubmed
,
Xenbase
Cachelin,
Beta-subunits co-determine the sensitivity of rat neuronal nicotinic receptors to antagonists.
1995,
Pubmed
,
Xenbase
Charnet,
An open-channel blocker interacts with adjacent turns of alpha-helices in the nicotinic acetylcholine receptor.
1990,
Pubmed
Cohen,
Mutations in M2 alter the selectivity of the mouse nicotinic acetylcholine receptor for organic and alkali metal cations.
1992,
Pubmed
,
Xenbase
Conroy,
The alpha 5 gene product assembles with multiple acetylcholine receptor subunits to form distinctive receptor subtypes in brain.
1992,
Pubmed
Corriveau,
Coexpression of multiple acetylcholine receptor genes in neurons: quantification of transcripts during development.
1993,
Pubmed
Fieber,
Acetylcholine-evoked currents in cultured neurones dissociated from rat parasympathetic cardiac ganglia.
1991,
Pubmed
Francis,
Muscle-type nicotinic acetylcholine receptor delta subunit determines sensitivity to noncompetitive inhibitors, while gamma subunit regulates divalent permeability.
1996,
Pubmed
,
Xenbase
Francis,
Sensitivity to voltage-independent inhibition determined by pore-lining region of the acetylcholine receptor.
1998,
Pubmed
,
Xenbase
Giraudat,
Structure of the high-affinity binding site for noncompetitive blockers of the acetylcholine receptor: serine-262 of the delta subunit is labeled by [3H]chlorpromazine.
1986,
Pubmed
Horton,
Engineering hybrid genes without the use of restriction enzymes: gene splicing by overlap extension.
1989,
Pubmed
Hussy,
Agonist and antagonist effects of nicotine on chick neuronal nicotinic receptors are defined by alpha and beta subunits.
1994,
Pubmed
,
Xenbase
KATZ,
A study of the desensitization produced by acetylcholine at the motor end-plate.
1957,
Pubmed
Labarca,
Channel gating governed symmetrically by conserved leucine residues in the M2 domain of nicotinic receptors.
1995,
Pubmed
,
Xenbase
Leonard,
Evidence that the M2 membrane-spanning region lines the ion channel pore of the nicotinic receptor.
1988,
Pubmed
,
Xenbase
Luetje,
Both alpha- and beta-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors.
1991,
Pubmed
,
Xenbase
Luetje,
Neurotoxins distinguish between different neuronal nicotinic acetylcholine receptor subunit combinations.
1990,
Pubmed
,
Xenbase
Neher,
Local anaesthetics transiently block currents through single acetylcholine-receptor channels.
1978,
Pubmed
Papke,
Activation and inhibition of rat neuronal nicotinic receptors by ABT-418.
1997,
Pubmed
,
Xenbase
Papke,
The kinetic properties of neuronal nicotinic receptors: genetic basis of functional diversity.
1993,
Pubmed
Papke,
Inhibition of nicotinic acetylcholine receptors by bis (2,2,6,6-tetramethyl- 4-piperidinyl) sebacate (Tinuvin 770), an additive to medical plastics.
1994,
Pubmed
,
Xenbase
Papke,
Partial agonist properties of cytisine on neuronal nicotinic receptors containing the beta 2 subunit.
1994,
Pubmed
,
Xenbase
Revah,
Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor.
1991,
Pubmed
,
Xenbase
Rozental,
Agonist recognition site of the peripheral acetylcholine receptor ion channel complex differentiates the enantiomers of nicotine.
1989,
Pubmed
STONE,
Ganglionic blocking properties of 3-methylaminoisocamphane hydrochloride (mecamylamine): a secondary amine.
1956,
Pubmed
Sanger,
DNA sequencing with chain-terminating inhibitors.
1977,
Pubmed
Sine,
Agonists block currents through acetylcholine receptor channels.
1984,
Pubmed
Varanda,
The acetylcholine receptor of the neuromuscular junction recognizes mecamylamine as a noncompetitive antagonist.
1985,
Pubmed
Vernallis,
Neurons assemble acetylcholine receptors with as many as three kinds of subunits while maintaining subunit segregation among receptor subtypes.
1993,
Pubmed
Woodhull,
Ionic blockage of sodium channels in nerve.
1973,
Pubmed
de Fiebre,
Characterization of a series of anabaseine-derived compounds reveals that the 3-(4)-dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha 7/125I-alpha-bungarotoxin receptor subtypes.
1995,
Pubmed
,
Xenbase
