Fish ASIC1 (fASIC1) cloned from Opsanus tau, unlike the rat ASICs, requires Ca(2+) in the extracellular preconditioning solution (pH 7.4) to be activated. Here we show that fASIC1 is interacting with Ca(2+) in the same way as mammalian ASICs: extracellular Ca(2+) is increasing the proportion of channels available for activation by stabilizing the closed state of the channel; in the activation process Ca(2+) is released; H(+) compete for the binding site of Ca(2+) making the gating mechanism both Ca(2+) and H(+) dependent; H(+) stabilizes the desensitized state; Ca(2+) blocks the fASIC1 channel; and the affinity of the block is also modulated by H(+). The "Ca(2+) activation requirement" of fASIC1 reflects its greater affinity for steady-state desensitization by H(+) compared to mammalian ASIC1.