Here we report a 26- to 29-pS cation channel abundantly expressed in freshly isolated and primary cultured type II cells from rat or healthy human lungs. The channel was never spontaneously active in cell-attached patches but could be activated by cell permeabilization with beta-escin. Excised patch-clamp experiments revealed activation by Ca(2+) concentrations at the cytoplasmic side in the micromolar range. High concentrations of amiloride (>10 microM) at the extracellular side did not inhibit. The channel was equally permeable for K(+) and Na(+) but was essentially impermeable for Cl(-), Ca(2+), and Mg(2+). It was blocked by adenosine nucleotides (cytoplasmic side) with the following order of potency: AMP approximately ADP (EC(50) </= 10 microM) > ATP >> adenosine >> cyclic AMP. The blocking effect of ATP was reproduced by its nonhydrolyzable analogs AMPPNP or ATP-gamma-S. GTP did not inhibit. Cd(2+) blocked the channel with an EC(50) approximately 55.5 nM. We conclude that type II cells express a Ca(2+)-dependent, nucleotide-inhibited, nonselective, and Ca(2+)-impermeable cation channel (NSC(Ca/AMP)) with tonically suppressed activity. RT-PCR confirmed expression of TRPM4b, a channel with functional characteristics almost identical with NSC(Ca/AMP). Potential physiological roles are discussed.