Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
Br J Pharmacol. 2018 Jun;175(11):1838-1854. doi: 10.1111/bph.13851. Epub 2017 Jun 8.
GAT107 ((3aR,4S,9bS)-4-(4-bromo-phenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta-[c]quinoline-8-sulfonamide) is a positive allosteric modulator (PAM) and agonist of α7 nicotinic acetylcholine receptors (nAChRs)that can cause a prolonged period of primed potentiation of acetylcholine responses after drug washout. NS6740 is a silent agonist of α7 nAChRs that has little or no efficacy for activating the ion channel but induces stable desensitization states, some of which can be converted into channel-active states by PAMs. Although GAT107 and NS6740 appear to stably induce different non-conducting states, both agents are effective treatment for inflammation and inflammatory pain models. We sought to better understand how both of these drugs that have opposite effects on channel activation could regulate signal transduction.
Voltage-clamp experiments were conducted with α7 nAChRs expressed in Xenopus oocytes.
Long-lived sensitivity to a PAM or to an agonist was produced by NS6740 or GAT107 respectively. With sequential applications, these two drugs induced varying levels of persistent activation, which is a unique condition for a receptor that is known for rapid desensitization. The non-conducting states induced by NS6740 or GAT107 differ in their sensitivity to an α7 nAChR-selective antagonist and in how effectively they promote current.
CONCLUSIONS & IMPLICATIONS: Our data suggest that the persistent currents represent a dynamic interconversion between different stable desensitized states and the PAM-inducible conducting states. However, the similarity of NS6740 and GAT107 effects on inflammation and pain suggests that the different stable non-conducting states have common activity on signal transduction.
This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.
GAT107((3aR,4S,9bS)-4-(4-溴苯基)-3a,4,5,9b-四氢-3H-环戊[c]喹啉-8-磺酰胺)是一种正变构调节剂(PAM)和α7 烟碱型乙酰胆碱受体(nAChRs)的激动剂，可在药物洗脱后引起乙酰胆碱反应的长时间持续增强。NS6740 是一种α7 nAChRs 的沉默激动剂，对激活离子通道几乎没有或没有功效，但诱导稳定的脱敏状态，其中一些状态可通过 PAMs 转化为通道活性状态。尽管 GAT107 和 NS6740 似乎稳定地诱导不同的非传导状态，但两者都是炎症和炎症性疼痛模型的有效治疗药物。我们试图更好地理解这两种对通道激活有相反作用的药物如何调节信号转导。
用 Xenopus oocytes 中表达的 α7 nAChRs 进行电压钳实验。
NS6740 或 GAT107 分别产生对 PAM 或激动剂的长时敏感性。通过连续应用，这两种药物诱导了不同水平的持续激活，这是一种快速脱敏的受体的独特状态。NS6740 或 GAT107 诱导的非传导状态在其对 α7 nAChR 选择性拮抗剂的敏感性和促进电流的有效性方面存在差异。
我们的数据表明，持续电流代表不同稳定脱敏状态与 PAM 诱导的传导状态之间的动态相互转换。然而，NS6740 和 GAT107 对炎症和疼痛的作用相似表明，不同的稳定非传导状态在信号转导中具有共同的活性。
本文是关于烟碱型乙酰胆碱受体的专题部分的一部分。要查看本部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc。
