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. Issue 3 (19th April 2020)

• Record Type: Journal Article
• Authors: Vulfius, Catherine A.; Lebedev, Dmitrii S.; Kryukova, Elena V.; Kudryavtsev, Denis S.; Kolbaev, Sergey N.; Utkin, Yuri N.; Tsetlin, Victor I.
• Is Part Of: Journal of neurochemistry. Volume 155:Issue 3(2020)
• Page Start: 274
• Page End: 284
• Publication Date: 2020-04-19
• Subjects: chloride conductance -- computer modeling -- docking simulation -- ligand‐gated channels -- Lymnaea neurons -- PNU‐120596 modulation; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15020
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: 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 GABAA Rs 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. Abstract : Our aim was probing the effects of PNU‐120596, a positive allosteric modulator (PAM) of α7 nicotinic acetylcholine receptors (nAChR), on the anion‐conducting channels. Experiments were performed on Lymnaea stagnalis and rat Purkinje neurons and mammalian receptors expressed in Xenopus oocytes or PC12 cells. In Lymnaea neurons, PNU‐120596, contrary to α7 nAChR, inhibited chloride currents mediated by two nAChR subtypes, GABA and glutamate receptors; one nAChR subtype demonstrated a strong acceleration of desensitization. With the mammalian glycine and GABAA receptors, PNU‐120596 was a weak PAM. Thus, our results provide new information about the dependence of PAM action on the receptor structure.