The apical membrane of larval bullfrog skin contains a nonselective cation channel that can be activated by apically applied amiloride and acetylcholine. In our search for other ligands that might activate this channel, ATP and other purinergics were tested. When ATP (10-1,000 ยตM) was added to the apical side of tadpole skin mounted in a modified Ussing chamber, there was a transient increase in short circuit current (Isc). The increase in Isc occurred with either Na or K as the dominant cation in the apical solution. The response was larger in a calcium-free Ringer. ADP and AMP had similar but smaller effects than ATP. Adenosine and UTP were without effect. The ATP response was blocked by W-7, atropine, curare, diltiazem, and suramin. These blockers also inhibit amiloride stimulation of Isc, suggesting that ATP activates a related transport pathway. Studies with analogs of ATP suggest that the ATP binding site in tadpole skin has characteristics in common with the P2x receptor found in other tissues. These results demonstrate that in addition to amiloride and acetylcholine, ATP stimulates cation transport at the apical membrane of larval amphibian skin epithelia.