Interaction of Bupropion with Muscle-Type Nicotinic Acetylcholine Receptors in Different Conformational States
Interaction of Bupropion with Muscle-Type Nicotinic Acetylcholine Receptors in Different Conformational States
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DOI：
10.1021/bi802206k
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发表时间：
2009-06-02
期刊：
影响因子：
2.9
通讯作者：
Bouzat, Cecilia
中科院分区：
文献类型：
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作者：
Arias, Hugo R.;Gumilar, Fernanda;Bouzat, Cecilia
为了表征安非他酮对肌肉型烟碱乙酰胆碱受体（AChRs）的结合位点和抑制机制，采用结构和功能方法。结果证实，安非他酮（a）抑制胚胎肌肉AChR中表巴替啶诱导的Ca（2+）内流，（B）抑制静息/可激活状态下的成人肌肉AChR宏观电流，其效力比开放状态下高100倍，（c）增加成人肌肉AChR从开放状态的脱敏速率，并损害通道从静息状态的开放，（d）抑制[（3）H]TCP和[（3）H]丙咪嗪与脱敏的/氨甲酰胆碱结合的电鳐AChR的结合，其亲和力高于静息的/α-银环蛇毒素结合的AChR，（e）主要通过熵驱动的过程与任一状态的电鳐AChR结合，和（f）通过货车德瓦耳斯网络、氢键和极性相互作用与位于丝氨酸（6 '位）和缬氨酸（13'位）环之间的结合结构域相互作用。总的来说，我们的数据表明，安非他酮首先结合到休息乙酰胆碱受体，降低离子通道开放的概率。随后通过加速脱敏过程来减少开放离子通道的残余分数。安非他酮与PCP共享的位于丝氨酸和缬氨酸环之间的管腔结合结构域相互作用，并且这种相互作用主要由熵驱动的过程介导。
To characterize the binding sites and the mechanisms of inhibition of bupropion on muscle-type nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The results established that bupropion (a) inhibits epibatidine-induced Ca(2+) influx in embryonic muscle AChRs, (b) inhibits adult muscle AChR macroscopic currents in the resting/activatable state with similar to 100-fold higher potency compared to that in the open state, (c) increases the desensitization rate of adult muscle AChRs from the open state and impairs channel opening from the resting state, (d) inhibits binding of [(3)H]TCP and [(3)H]imipramine to the desensitized/carbamylcholine-bound Torpedo AChR with higher affinity compared to the resting/alpha-bungarotoxin-bound AChR, (e) binds to the Torpedo AChR in either state mainly by an entropy-driven process, and (f) interacts with a binding domain located between the serine (position 6') and valine (position 13') rings, by a network of van der Waals, hydrogen bond, and polar interactions. Collectively, our data indicate that bupropion first binds to the resting AChR, decreasing the probability of ion channel opening. The remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process. Bupropion interacts with a luminal binding domain shared with PCP that is located between the serine and valine rings, and this interaction is mediated mainly by an entropy-driven process.