Isomeric yohimbine alkaloids block calcium-activated K⁺ channels in medullary thick ascending limb cells of rabbit kidney

The alpha₂-adrenergic antagonist yohimbine (YOH) and the closely related isomers corynanthine (COR) and rauwolscine (RAU) caused brief interruptions in current characteristic of a fast blocker Ca²⁺-activated K⁺ channels in cultured medullary thick ascending limb (MTAL) cells. The apparent dissociation constants (K_app), for COR, YOH, and RAU, respectively, at the intracellular face of the channel in the presence of 200 mm K⁺ are 45±1, 98±2, and 310±33 μm. The K_app for COR on the extracellular side also in the presence of 200 mm. K⁺ was much greater at 1.6±0.17 mm. Increasing K⁺ on the same side as the blocker relieves the blocking reaction. The K_app for the alkaloids varies with K⁺ in a manner quantitatively consistent with K⁺ and the alkaloids competing for a common binding site. Finally, blocking by the charged form of these alkaloids is voltage dependent with changes in K_app of 86±7 and 94±6 μm per e-fold change in voltage for blockers applied either from the inside or outside. The alkaloids block at an electrical distance similar to tetraethylammonium, suggesting that the site within the channel pore of these molecules may be similar.