title: The dual effect of PNU-120596 on α7 nicotinic acetylcholine receptor channels.
abstract: PNU-120596 (1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea), a Type-II positive allosteric modulator of α(7) nicotinic acetylcholine receptors inhibits α(7) desensitization and robustly prolongs openings of α(7) channels. However, these effects may render α(7) channels more accessible to positively charged molecules and thus, more susceptible to voltage-dependent open-channel-block-like inhibition. To test this hypothesis, choline chloride (i.e., choline), a selective endogenous α(7) agonist, and bicuculline methochloride (i.e., bicuculline), a competitive α(7) antagonist, were used as membrane voltage-sensitive probes in whole-cell voltage-clamp recordings from hippocampal CA1 interneurons in acute brain slices in the absence and presence of PNU-120596. PNU-120596 enhanced voltage-dependent inhibition of α(7) responses by bicuculline and choline. In the presence of PNU-120596, α(7) channels favored a burst-like kinetic modality in the presence, but not absence of bicuculline and bursts of α(7) openings were voltage-dependent. These results suggest that PNU-120596 alters the pharmacology of α(7) channels by making these channels more susceptible to voltage-dependent inhibitory interactions with positively charged drugs at concentrations that do not potently inhibit α(7) channels without PNU-120596. This inhibition imitates α(7) nicotinic receptor desensitization and compromises the potentiating anti-desensitization effects of PNU-120596 on α(7) nicotinic receptors. This unexpected dual action of PNU-120596, and possibly other Type-II positive allosteric modulators of α(7) nicotinic receptors, may lead to unanticipated α(7) channel-drug interactions and misinterpretation of α(7) single-channel data.
authors.affiliation: Southern Illinois University School of Medicine, Department of Pharmacology, MC #9629, PO Box 19629, Springfield, IL 62702, United States.
authors.forename: Bopanna I
authors.initials: BI
authors.lastname: Kalappa
authors.forename: Victor V
authors.initials: VV
authors.lastname: Uteshev
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000031:analogs & derivatives / Q000494:pharmacology; D002794:Choline / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D010671:Phenylurea Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D007555:Isoxazoles; D010671:Phenylurea Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; C017069:bicuculline methiodide; D002794:Choline; D001640:Bicuculline
keywords: Bicuculline; Channel block; Choline; Desensitization; PNU-120596; PNU120596; α(7) Nicotinic receptor
references.citation: Brain Res. 2002 Sep 6;948(1-2):33-46
references.pmid: 12383953
references.citation: Mol Pharmacol. 2011 Dec;80(6):1013-32
references.pmid: 21885620
references.citation: Neuropharmacology. 1997 Nov-Dec;36(11-12):1653-7
references.pmid: 9517436
references.citation: Front Pharmacol. 2011 Dec 27;2:81
references.pmid: 22207849
references.citation: Acta Biochim Biophys Sin (Shanghai). 2010 Jan;42(1):8-20
references.pmid: 20043042
references.citation: Mol Pharmacol. 2007 Sep;72(3):715-24
references.pmid: 17565004
references.citation: J Neurosci. 1999 Apr 1;19(7):2693-705
references.pmid: 10087082
references.citation: Neuropharmacology. 2001 Dec;41(7):854-61
references.pmid: 11684149
references.citation: Brain Res. 2000 Nov 3;882(1-2):155-68
references.pmid: 11056195
references.citation: PLoS One. 2012;7(3):e32951
references.pmid: 22479351
references.citation: J Pharmacol Exp Ther. 2010 Feb;332(2):588-98
references.pmid: 19923442
references.citation: Eur J Neurosci. 1997 Dec;9(12):2734-42
references.pmid: 9517478
references.citation: J Neurosci. 2005 Apr 27;25(17):4396-405
references.pmid: 15858066
references.citation: Pflugers Arch. 1996 Aug;432(4):607-13
references.pmid: 8764960
references.citation: Adv Exp Med Biol. 2012;740:603-38
references.pmid: 22453962
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14686-91
references.pmid: 18791069
references.citation: Br J Pharmacol. 2002 Sep;137(1):49-61
references.pmid: 12183330
references.citation: PLoS One. 2010 Nov 12;5(11):e13964
references.pmid: 21103043