Andersen Natalia D, Nielsen Beatriz E, Corradi Jeremías, Tolosa María F, Feuerbach Dominik, Arias Hugo R, Bouzat Cecilia
Universidad Nacional del Sur/CONICET, Instituto de Investigaciones Bioquímicas de Bahía Blanca, Bahía Blanca 8000, Argentina.
Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Neuropharmacology. 2016 Aug;107:189-200. doi: 10.1016/j.neuropharm.2016.02.032. Epub 2016 Feb 27.
Enhancement of α7 nicotinic receptor (nAChR) function by positive allosteric modulators (PAMs) is a promising therapeutic strategy to improve cognitive deficits. PAMs have been classified only on the basis of their macroscopic effects as type I, which only enhance agonist-induced currents, and type II, which also decrease desensitization and reactivate desensitized nAChRs. To decipher the molecular basis underlying these distinct activities, we explored the effects on single-α7 channel currents of representative members of each type and of less characterized compounds. Our results reveal that all PAMs enhance open-channel lifetime and produce episodes of successive openings, thus indicating that both types affect α7 kinetics. Different PAM types show different sensitivity to temperature, suggesting different mechanisms of potentiation. By using a mutant α7 receptor that is insensitive to the prototype type II PAM (PNU-120596), we show that some though not all type I PAMs share the structural determinants of potentiation. Overall, our study provides novel information on α7 potentiation, which is key to the ongoing development of therapeutic compounds.
通过正变构调节剂（PAM）增强α7烟碱型受体（nAChR）功能是改善认知缺陷的一种有前景的治疗策略。PAM仅根据其宏观效应被分为I型，即仅增强激动剂诱导的电流，和II型，即还减少脱敏并使脱敏的nAChR重新激活。为了解释这些不同活性背后的分子基础，我们探究了每种类型的代表性成员以及特征较少的化合物对单α7通道电流的影响。我们的结果表明，所有PAM均延长开放通道寿命并产生连续开放的片段，因此表明这两种类型均影响α7动力学。不同类型的PAM对温度表现出不同的敏感性，提示不同的增强机制。通过使用对原型II型PAM（PNU-120596）不敏感的突变α7受体，我们表明一些（但并非全部）I型PAM具有共同的增强结构决定因素。总体而言，我们的研究提供了关于α7增强作用的新信息，这对于正在进行的治疗化合物开发至关重要。
