The early H(+)-induced current in the embryonic spinal cord neurone depends on extracellular Ca(2+) for its function. We have studied the Ca(2+)-dependence of homo- and heteromultimeric acid-sensing ion channels (ASICs) expressed in Cos cells. It was found that single-channel conductance of both the ASIC2a and the ASIC1a channel is reduced at membrane potentials more negative than -40 mV by elevated extracellular Ca(2+). Due to this effect on unitary currents, the macroscopic ASIC2a peak current at -60 mV decreases gradually with rising extracellular Ca(2+) concentration. In addition, the macroscopic ASIC1a current is very small at low extracellular Ca(2+) and increases with rising Ca(2+) up to 5 mM before decreasing again at still higher concentrations of extracellular Ca(2+).