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

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.