Tetrahydroaminoacridine (tacrine) is an anticholinesterase agent used in the treatment of Alzheimer's disease. Its effectiveness against dementia is attributed to its inhibition of acetylcholine breakdown in the synaptic cleft. Tacrine has also been shown to block ionic currents, including many types of potassium (K+) currents, calcium currents, and sodium currents. However, the physiologic significance of this blockade, especially with respect to its effectiveness against Alzheimer's disease, is not clear because of relatively high (several hundred micromolar to millimolar) concentrations of tacrine employed in many studies of channel blockade, and because it blocks several types of currents. A complete mutational and pharmacologic resolution of ionic currents in the larval muscles of Drosophila allowed us to examine the selectivity of tacrine's effects at very low concentrations. At concentrations as low as 10 microM, tacrine selectively blocked the delayed rectifier K+ current without affecting the three other K+ currents or the calcium channel current in these cells. It also increased the duration of the action potentials significantly. An interesting aspect of tacrine's selectivity is that the current blocked by it is the quinidine-sensitive delayed rectifier K+ current rather than the 4-aminopyridine (4-AP)-sensitive transient K+ current. This is in contrast to the generally emphasized structural relationship between tacrine and 4-AP. Since tacrine is structurally related to quinidine as well, these observations suggest a structural basis for the selectivity of tacrine, 4-AP, and quinidine for specific K+ channels. Furthermore, the data are consistent with the possibility of increased neurotransmitter release, due to prolonged presynaptic action potentials, acting synergistically with the anticholinesterase activity of tacrine to increase its therapeutic effectiveness.