Iptakalim as a human nicotinic acetylcholine receptor antagonist
Iptakalim as a human nicotinic acetylcholine receptor antagonist
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DOI：
10.1124/jpet.jpet.105.094987
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发表时间：
2006-02-01
影响因子：
3.5
通讯作者：
Wu, J
中科院分区：
文献类型：
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作者：
Hu, J;Lindenberger, K;Wu, J
烟碱乙酰胆碱受体 (nAChR) 在神经系统功能中发挥着许多关键作用，并与多种疾病有关。作用于 nAChR 的药物，可能以 nAChR 亚型选择性方式，可用于剖析受体功能，也可能作为药物。在本研究中，我们使用膜片钳全细胞记录和药理学操作来评估盐酸伊他卡林（Ipt）的作用，据报道，该药物可作为 ATP 敏感钾（K-ATP）通道开放剂，对在天然 nAChR 缺失的 SH-EP1 人上皮细胞系中异源表达的选定人 nAChR 的影响。 Ipt 降低了人 α4β-2nAChR 响应烟碱激动剂介导的峰值和稳态全细胞电流幅度。它还加速电流衰减，导致激动剂的表观功效下降，并以电压和使用依赖性方式作用于 α4β2-nAChR。这些发现以及 Ipt 无法阻断放射性标记的皮巴替丁与 α4β2-nAChR 的结合表明了一种非竞争性拮抗机制。其他研究低估了 Ipt 对 nAChR 内化或 K ATP 通道参与 Ipt 诱导的 α4β2-nAChR 功能抑制的影响。相比之下，α 7-nAChR 对作为拮抗剂的 Ipt 的敏感性低于 α 4 β 2-nAChR。因此，α4β-2nAChR 是 Ipt 的分子靶标之一，Ipt 可作为 nAChR 功能表征和药理学分析的工具。
Nicotinic acetylcholine receptors ( nAChRs) play many critical roles in nervous system function and have been implicated in a variety of diseases. Drugs acting at nAChRs, perhaps in nAChR subtype-selective manners, can be used to dissect receptor function and perhaps as medications. In the present study, we used patch-clamp whole-cell recording and pharmacological manipulations to evaluate effects of iptakalim hydrochloride ( Ipt), which is a drug reported to act as an ATP-sensitive potassium ( K-ATP) channel opener, on selected human nAChRs heterologously expressed in the native nAChR-null SH-EP1 human epithelial cell line. Ipt reduced both peak and steadystate whole-cell current amplitudes mediated by human alpha 4 beta-2nAChRs in response to nicotinic agonists. It also accelerated current decay, caused a decline in apparent efficacy of agonists, and acted in voltage-and use-dependent manners at alpha 4 beta 2-nAChRs. These findings and the inability of Ipt to block radiolabeled epibatidine binding to alpha 4 beta 2-nAChRs suggest a noncompetitive mechanism of antagonism. Other studies discount effects of Ipt on nAChR internalization or involvement of K ATP channels in Ipt-induced inhibition of alpha 4 beta 2-nAChR function. By comparison, alpha 7-nAChRs were less sensitive than alpha 4 beta 2-nAChRs to Ipt acting as an antagonist. Thus, alpha 4 beta-2nAChRs are among the molecular targets of Ipt, which has utility as a tool in functional characterization and pharmacological profiling of nAChRs.