We previously cloned Na+/Ca2+exchanger (NCX1) from mesangial cells of salt-sensitive (SNCX = NCX1.7) and salt-resistant (RNCX = NCX1.3) Dahl/Rapp rats. The abilities of these isoforms to regulate cytosolic Ca2+concentration ([Ca2+]i) were assessed in fura 2-loaded OK cells expressing the vector (VOK), RNCX (ROK), and SNCX (SOK). Baseline [Ca2+]iwas 98 ± 20 nM (n = 12) in VOK and was significantly lower in ROK (44 ± 5 nM; n = 12) and SOK (47 ± 13 nM; n = 12) cells. ATP at 100 μM increased [Ca2+]iby 189 ± 55 nM (n = 12), 21 ± 9 nM (n = 12), and 69 ± 18 nM (n = 12) in VOK, ROK, and SOK cells, respectively. ATP (1 mM) or bradykinin (0.1 mM) caused large increases in [Ca2+]iand ROK but not SOK cells were much more efficient in reducing [Ca2+]iback to baseline levels. Parental Sprague-Dawley rat mesangial cells express both RNCX (SDRNCX) and SNCX (SDSNCX). SDRNCX and RNCX are identical at every amino acid residue, but SDSNCX and SNCX differ at amino acid 218 where it is isoleucine in SDSNCX and not phenylalanine. OK cells expressing SD-SNCX (SDSOK) reduced ATP (1 mM)-induced [Ca2+]iincrease back to baseline at a rate equivalent to that for ROK cells. PKC downregulation significantly attenuated the rate at which ROK and SDSOK cells reduced ATP-induced [Ca2+]iincrease but had no effect in SOK cells. The reduced efficiency of SNCX to regulate [Ca2+]iis attributed, in part, to the isoleucine-to-phenylalanine mutation at amino acid 218.