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 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.