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The use of PNU-120596 [1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea], a positive allosteric modulator of alpha7 nicotinic acetylcholine receptor (nAChR), may be beneficial for enhancing cholinergic therapies. However, the effects of PNU-120596 on activation of native alpha7-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 ( approximately 10 microM) elicited repetitive step-like whole-cell responses reminiscent of single ion channel openings that were reversibly blocked by 20 nM methyllycaconitine, a selective alpha7 nAChR antagonist. The effects of choline and PNU-120596 were synergistic as administration of 10 to 40 microM choline or 1 to 4 muM PNU-120596 alone did not elicit responses. In voltage clamp at -60 mV, the persistent activation of alpha7-containing nAChRs by 10 microM choline plus 1 microM PNU-120596 was estimated to produce a sustained influx of Ca(2+) ions at a rate of 8.4 pC/min ( approximately 0.14 pA). In the presence of PNU-120596 in current clamp, transient step-like depolarizations ( approximately 5 mV) enhanced neuronal excitability and triggered voltage-gated conductances; a single opening of an alpha7-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 alpha7-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.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

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]