Physiological concentrations of choline activate native α7-containing nicotinic acetylcholine receptors in the presence of PNU-120596 [1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea]

Alexander G. Gusev, Victor V. Uteshev

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


The use of PNU-120596 [1-(5-chloro-2,4-dimethoxyphenyl)-3-(5- methylisoxazol-3-yl)-urea], a positive allosteric modulator of α7 nicotinic acetylcholine receptor (nAChR), may be beneficial for enhancing cholinergic therapies. However, the effects of PNU-120596 on activation of native α7-containing nAChRs by physiological concentrations of choline are not known and were investigated in this study using patch-clamp electrophysiology and histaminergic tuberomammillary neurons in hypothalamic slices. In the presence of PNU-120596, subthreshold (i.e., inactive) physiological concentrations of choline (-10 μM) elicited repetitive step-like whole-cell responses reminiscent of single ion channel openings that were reversibly blocked by 20 nM methyllycaconitine, a selective α7 nAChR antagonist. The effects of choline and PNU-120596 were synergistic as administration of 10 to 40 μM choline or 1 to 4 μM PNU-120596 alone did not elicit responses. In voltage clamp at -60 mV, the persistent activation of α7-containing nAChRs by 10 μM choline plus 1 μM PNU-120596 was estimated to produce a sustained influx of Ca2+ ions at a rate of 8.4 pC/min (-0.14 pA). In the presence of PNU-120596 in current clamp, transient step-like depolarizations (-5 mV) enhanced neuronal excitability and triggered voltage-gated conductances; a single opening of an α7-containing nAChR channel appeared to transiently depolarize the entire neuron and facilitate spontaneous firing. Therefore, this study tested and confirmed the hypothesis that PNU-120596 enhances the effects of subthreshold concentrations of choline on native α7-containing nAChRs, allowing physiological levels of choline to activate these receptors and produce whole-cell responses in the absence of exogenous nicotinic agents. In certain neurological disorders, this activation may be therapeutically beneficial, more efficacious, and safer than treatments with nAChR agonists.

Original languageEnglish
Pages (from-to)588-598
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - Feb 2010


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