Na(+)/Ca(2+)-K(+) exchange (NCKX) was first discovered in the outer segments of vertebrate rod photoreceptors (ROS), where it is the only mechanism for extruding the Ca(2+) that enters ROS via the light-sensitive and cGMP-gated channels. ROS NCKX1 is the only NCKX gene family member studied extensively in situ. ROS NCKX1 cDNAs have been cloned subsequently from a number of species including man and shown to be the first member of a new gene family ( SLCA24). Three further members of the human NCKX gene family have been cloned subsequently ( NCKX2- 4) by homology with NCKX1, while a partial sequence of a fifth human NCKX gene has appeared in the data base. NCKX-related genes have also been identified in lower animals including fruit flies, worms and sea urchins. NCKX2 is expressed in the brain, in retinal cone photoreceptors and in retinal ganglion cells, while NCKX3 and NCKX4 show a broader expression pattern. In situ NCKX1 and heterologously expressed NCKX2 operate at a 4Na(+):1Ca(2+)+1 K(+) stoichiometry; both NCKX1 and NCKX2 are bidirectional transporters normally extruding Ca(2+) from the cell (forward exchange), but also able to carry Ca(2+) into the cell (reverse exchange) when the transmembrane Na(+) gradient is reversed. Sequence changes have been observed for both NCKX1 and NCKX2 in patients with retinal diseases, but a definitive association with retinal disease has not been shown.