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PNU-120596, a positive allosteric modulator of mammalian α7 nicotinic acetylcholine receptor, is a negative modulator of ligand-gated chloride-selective channels of the gastropod Lymnaea stagnalis.
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2020-04-04 , DOI: 10.1111/jnc.15020 Catherine A Vulfius 1 , Dmitrii S Lebedev 2 , Elena V Kryukova 2 , Denis S Kudryavtsev 2 , Sergey N Kolbaev 3 , Yuri N Utkin 2 , Victor I Tsetlin 2
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2020-04-04 , DOI: 10.1111/jnc.15020 Catherine A Vulfius 1 , Dmitrii S Lebedev 2 , Elena V Kryukova 2 , Denis S Kudryavtsev 2 , Sergey N Kolbaev 3 , Yuri N Utkin 2 , Victor I Tsetlin 2
Affiliation
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Excitatory α7 neuronal nicotinic receptors (nAChR) are widely expressed in the central and peripheral nervous and immune systems and are important for learning, memory, and immune response regulation. Specific α7 nAChR ligands, including positive allosteric modulators are promising to treat cognitive disorders, inflammatory processes, and pain. One of them, PNU‐120596, highly increased the neuron response to α7 agonists and retarded desensitization, showing selectivity for α7 as compared to heteromeric nAChRs, but was not examined at the inhibitory ligand‐gated channels. We studied PNU‐120596 action on anion‐conducting channels using voltage‐clamp techniques: it slightly potentiated the response of human glycine receptors expressed in PC12 cells, of rat GABAA receptors in cerebellar Purkinje cells and mouse GABAARs heterologously expressed in Xenopus oocytes. On the contrary, PNU‐120596 exerted an inhibitory effect on the receptors mediating anion currents in Lymnaea stagnalis neurons: two nAChR subtypes, GABA and glutamate receptors. Acceleration of the current decay, contrary to slowing down desensitization in mammalian α7 nAChR, was observed in L. stagnalis neurons predominantly expressing one of the two nAChR subtypes. Thus, PNU‐120596 effect on these anion‐selective nAChRs was just opposite to the action on the mammalian cation‐selective α7 nAChRs. A comparison of PNU‐120596 molecule docked to the models of transmembrane domains of the human α7 AChR and two subunits of L. stagnalis nAChR demonstrated some differences in contacts with the amino acid residues important for PNU‐120596 action on the α7 nAChR. Thus, our results show that PNU‐120596 action depends on a particular subtype of these Cys‐loop receptors.
中文翻译：
PNU-120596是哺乳动物α7烟碱型乙酰胆碱受体的正变构调节剂，是腹足纲腹足Ly的配体门控氯化物选择性通道的负调节剂。
兴奋性α7神经元烟碱受体（nAChR）在中枢和外周神经和免疫系统中广泛表达，对学习，记忆和免疫应答调节至关重要。特定的α7nAChR配体（包括正变构调节剂）有望用于治疗认知障碍，炎症过程和疼痛。其中之一，PNU-120596，高度增加了对α7激动剂的神经元反应，并延缓了脱敏，与异聚nAChRs相比，对α7具有选择性，但未在抑制性配体门控通道上进行检查。我们使用电压钳技术研究了PNU-120596在阴离子传导通道上的作用：它稍微增强了大鼠GABA A在PC12细胞中表达的人类甘氨酸受体的反应。小爪浦肯野细胞中的受体和小鼠爪蟾卵母细胞中异源表达的小鼠GABA A Rs 。相反，PNU-120596对介导耻骨林神经元阴离子流的受体产生抑制作用：两种nAChR亚型，GABA和谷氨酸受体。与减慢哺乳动物α7nAChR的脱敏反应相反，在主要表达两种nAChR亚型之一的耻骨乳突神经元中观察到电流衰减的加速。因此，PNU-120596对这些阴离子选择性nAChRs的作用与对哺乳动物阳离子选择性α7nAChRs的作用正好相反。将PNU‐120596分子与人α7AChR的跨膜结构域模型和PPAR的两个亚基进行比较葡萄球菌nAChR在与PNU‐120596作用于α7nAChR的重要氨基酸残基接触方面表现出一些差异。因此，我们的结果表明，PNU-120596的作用取决于这些Cys-loop受体的特定亚型。
更新日期：2020-04-04
中文翻译：
PNU-120596是哺乳动物α7烟碱型乙酰胆碱受体的正变构调节剂，是腹足纲腹足Ly的配体门控氯化物选择性通道的负调节剂。
兴奋性α7神经元烟碱受体（nAChR）在中枢和外周神经和免疫系统中广泛表达，对学习，记忆和免疫应答调节至关重要。特定的α7nAChR配体（包括正变构调节剂）有望用于治疗认知障碍，炎症过程和疼痛。其中之一，PNU-120596，高度增加了对α7激动剂的神经元反应，并延缓了脱敏，与异聚nAChRs相比，对α7具有选择性，但未在抑制性配体门控通道上进行检查。我们使用电压钳技术研究了PNU-120596在阴离子传导通道上的作用：它稍微增强了大鼠GABA A在PC12细胞中表达的人类甘氨酸受体的反应。小爪浦肯野细胞中的受体和小鼠爪蟾卵母细胞中异源表达的小鼠GABA A Rs 。相反，PNU-120596对介导耻骨林神经元阴离子流的受体产生抑制作用：两种nAChR亚型，GABA和谷氨酸受体。与减慢哺乳动物α7nAChR的脱敏反应相反，在主要表达两种nAChR亚型之一的耻骨乳突神经元中观察到电流衰减的加速。因此，PNU-120596对这些阴离子选择性nAChRs的作用与对哺乳动物阳离子选择性α7nAChRs的作用正好相反。将PNU‐120596分子与人α7AChR的跨膜结构域模型和PPAR的两个亚基进行比较葡萄球菌nAChR在与PNU‐120596作用于α7nAChR的重要氨基酸残基接触方面表现出一些差异。因此，我们的结果表明，PNU-120596的作用取决于这些Cys-loop受体的特定亚型。
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