AN ACTIVATOR OF CALCIUM-DEPENDENT POTASSIUM CHANNELS ISOLATED FROM A MEDICINAL HERB

Large-conductance calcium-dependent potassium (maxi-K) channels play a n important role in regulating the tone of airway smooth muscle and th e release of bronchoconstrictive substances from nerves in the lung. C rude extracts of Desmodium adscendens, a medicinal herb used in Ghana as a treatment for asthma, inhibit binding of monoiodotyrosine charybd otoxin (I-125-ChTX) to receptor sites in bovine tracheal smooth muscle membranes that have been shown to be associated with maxi-K channels. Using this assay, three active components have been purified and iden tified by NMR and MS. Comparison with authentic samples revealed the t hree active components as the known triterpenoid glycosides dehydrosoy asaponin I (DHS-I), soyasaponin I, and soyasaponin III. The most poten t of these compounds, DHS-I, is a partial inhibitor of I-125-ChTX bind ing (K(i) = 120 nM, 62% maximum inhibition). Inhibition of I-125-ChTX binding is primarily due to a decrease in the observed maximum number of binding sites, with a smaller decrease in affinity. DHS-I increases the rate of toxin dissociation from its receptor, suggesting that mod ulation of ChTX binding occurs through an allosteric mechanism. DHS-I reversibly increases the open probability of maxi-K channels from bovi ne tracheal smooth muscle incorporated into planar lipid bilayers when applied to the intracellular, but not the extracellular, side of the membrane at concentrations as low as 10 nM. In contrast, DHS-I had no effect on several other types of potassium channels or membrane transp orters. This natural product is the first example of a high-affinity a ctivator of calcium-dependent potassium channels and is the most poten t known potassium channel opener.