The Na+/Ca2+ exchangers, RNCX and SNCX, were cloned from mesangial cells of salt sensitive and salt resistant Dahl/Rapp rats, respectively, and differ at amino acid 218 (RNCXi/SNCXf) and in the exons expressed at the alternative splice site (RNCX B, D/SNCXB, D, F). These isoforms are also expressed in myocytes, neurons, and astrocytes where they maintain cytosolic calcium homeostasis. We demonstrated that cells expressing SNCX were more susceptible to oxidative stress than cells expressing RNCX. Others demonstrated that amyloid β peptide (Aβ) augments the adverse effects of oxidative stress on calcium homeostasis. Therefore, we sought to assess the effect of Aβ 1-40 on the abilities of OK-PTH cells stably expressing RNCX and SNCX and human glioma cells, SKMG1, to regulate cytosolic calcium homeostasis. Our studies showed that Aβ 1-40 (1 μM) did not affect RNCX activity, as assessed by changes in [Ca2+]i (Δ[Ca2+]i, 260 ± 10 nM to 267 ± 8 nM), while stimulating exchange activity 2.4 and 3 fold in cells expressing SNCX (100 ± 8 to 244 ± 12 nM) and in SKMG1 cells (90 ± 11 nM to 270 ± 18 nM), respectively. Our results also showed that Aβ 1-40, while not affecting the rate of Mn 2+ influx in cells expressing RNCX, stimulated the rate of Mn 2+ influx 2.8 and 2.9 fold in cells expressing SNCX and in SKMG1 cells. Thus, our studies demonstrate that Aβ-induced cytosolic calcium increase is mediated through certain isoforms of the Na+/Ca 2+ exchanger and reveals a possible mechanism by which Aβ 1-40 can alter cytosolic calcium homeostasis. ©2005 Bentham Science Publishers Ltd.