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⁺]_i was 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⁺]_i by 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⁺]_i and ROK but not SOK cells were much more efficient in reducing [Ca²⁺]_i back 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 SDSNCX (SDSOK) reduced ATP (1 mM)-induced [Ca²⁺]_i increase 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⁺]_i increase but had no effect in SOK cells. The reduced efficiency of SNCX to regulate [Ca²⁺]_i is attributed, in part, to the isoleucine-to-phenylalanine mutation at amino acid 218.