The dual effect of PNU-120596 on α7 nicotinic acetylcholine receptor channels

• Published in: European journal of pharmacology Vol. 718; no. 1-3; pp. 226 - 234
• Main Authors: Kalappa, Bopanna I., Uteshev, Victor V.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.10.2013
• Subjects: alpha7 Nicotinic Acetylcholine Receptor - agonists; alpha7 Nicotinic Acetylcholine Receptor - antagonists & inhibitors; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Bicuculline; Bicuculline - analogs & derivatives; Bicuculline - pharmacology; Channel block; Choline; Choline - pharmacology; Desensitization; Drug Synergism; Female; In Vitro Techniques; Ion Channel Gating - drug effects; Isoxazoles - pharmacology; Male; Phenylurea Compounds - pharmacology; PNU-120596; PNU120596; Rats; Rats, Sprague-Dawley; α7 Nicotinic receptor; Desensitization; Choline; PNU-120596; α7 Nicotinic receptor; PNU120596; Channel block; Bicuculline; α Nicotinic receptor
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2013.08.027

PNU-120596 (1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea), a Type-II positive allosteric modulator of α7 nicotinic acetylcholine receptors inhibits α7 desensitization and robustly prolongs openings of α7 channels. However, these effects may render α7 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 α7 agonist, and bicuculline methochloride (i.e., bicuculline), a competitive α7 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 α7 responses by bicuculline and choline. In the presence of PNU-120596, α7 channels favored a burst-like kinetic modality in the presence, but not absence of bicuculline and bursts of α7 openings were voltage-dependent. These results suggest that PNU-120596 alters the pharmacology of α7 channels by making these channels more susceptible to voltage-dependent inhibitory interactions with positively charged drugs at concentrations that do not potently inhibit α7 channels without PNU-120596. This inhibition imitates α7 nicotinic receptor desensitization and compromises the potentiating anti-desensitization effects of PNU-120596 on α7 nicotinic receptors. This unexpected dual action of PNU-120596, and possibly other Type-II positive allosteric modulators of α7 nicotinic receptors, may lead to unanticipated α7 channel-drug interactions and misinterpretation of α7 single-channel data.