AbstractXE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone) is currently the most widely used and specific antagonist of the Kv7 (KCNQ) family of K+ channels. We report an unexpected antagonistic effect of this drug on ionotropic glycine receptors. In recordings of synaptic transmission in two brainstem nuclei (the medial nucleus of the trapezoid body and the dorsal cochlear nucleus), 10 μM XE991, a concentration typical for Kv7 studies in brain tissue, inhibited evoked glycinergic

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... ry postsynaptic currents (IPSCs) without altering paired-pulse ratio, and also reduced the amplitude of glycinergic miniature IPSCs. These results are indicative of a direct effect of the drug on postsynaptic glycine receptors. XE991 also produced dose-dependent block of the response to exogenously applied glycine, to a degree comparable to the block of synaptic transmission. Moreover, the drug inhibited homomeric glycine receptors expressed on presynaptic membrane of the calyx of Held. The degree of block was independent of glycine concentration, suggesting an allosteric interaction. The effects of XE991 on glycine responses are not likely to reflect block of the glycine-activated Cl- channels themselves, because block was voltage independent, and because GABA-activated Cl- currents were resistant to XE991 at concentrations up to 100 µM. Linopirdine, but not retigabine, also antagonized glycine receptor currents. Given the prevalence of glycine receptor signaling in the brain, these observations should be taken into account in studies of the roles of Kv7 channels in neural circuit function and disease.