Quinine blocks specific gap junction channel subtypes

We demonstrate that the antimalarial drug quinine specifically reduces curr ents through gap junctions formed by some connexins (Cx) in transfected mam malian cells, but does not affect other gap junction types, Quinine blocked Cx36 and Cx50 junctional currents in a reversible and concentration-depend ent manner with half maximal blocking concentrations of 32 and 73 muM, resp ectively; Hill coefficients for block by quinine were about 2 for both conn exins. In contrast, quinine did not substantially block gap junction channe ls formed by Cx26, Cx32, Cx40, and Cx43, and only moderately affected Cx45 junctions. To determine the location of the binding site of quinine (pKa = 8.7), we investigated the effect of quinine at various external and interna l pH values and the effect of a permanently charged quaternary derivative o f quinine. Our results indicate that the binding site for quinine is intrac ellular, possibly within the pore. Single-channel studies indicated that ex posure to quinine induced slow transitions between open and fully closed st ates that decreased open probability of the channel. Quinine thus offers a potentially useful method to block certain types of gap junction channels, including those between neurons that are formed by Cx36. Moreover, quinine derivatives that are excluded from other types of membrane channels may pro vide molecules with connexin-specific as well as connexin-selective blockin g activity.