Physiological concentrations of choline activate native alpha7-containing nicotinic acetylcholine receptors in the presence of PNU-120596 [1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea].

The Journal of Pharmacology and Experimental Therapeutics
Alexander G Gusev, Victor V Uteshev

Abstract

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-12059...Continue Reading

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Citations

Nov 2, 2012·The Journal of Pharmacology and Experimental Therapeutics·Kelen FreitasM Imad Damaj
Oct 1, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Corrie J B daCostaSteven M Sine
Feb 18, 2014·European Journal of Pharmacology·Victor V Uteshev
Feb 4, 2014·Neuropharmacology·Krisztina PestiE Sylvester Vizi
Nov 28, 2012·Brain Research Bulletin·Balázs LendvaiZsolt Némethy
Sep 17, 2013·European Journal of Pharmacology·Bopanna I Kalappa, Victor V Uteshev
Aug 18, 2017·Pain·Iboro C UmanaDaniel S McGehee
Feb 26, 2016·Molecular Neurobiology·Fen SunVictor V Uteshev
Feb 3, 2019·Translational Psychiatry·Ivanna IhnatovychKinga Szigeti

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