Antagonist activities of mecamylamine and nicotine show reciprocal dependence on beta subunit sequence in the second transmembrane domain.
Antagonist activities of mecamylamine and nicotine show reciprocal dependence on beta subunit sequence in the second transmembrane domain.
复制标题
美加明和尼古丁的拮抗活性显示出对第二跨膜结构域中的β亚基序列的相互依赖性。
DOI：
10.1038/sj.bjp.0702686
复制
发表时间：
1999
影响因子：
7.3
通讯作者：
Papke,RL
中科院分区：
文献类型：
--
作者：
Webster,JC;Francis,MM;Porter,JK;Robinson,G;Stokes,C;Horenstein,B;Papke,RL
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.British Journal of Pharmacology(1999)127, 1337–1348; doi:10.1038/sj.bjp.0702686
