Lanthanum is transported by the sodium/calcium exchanger and regulates its activity

La3+ uptake was measured in fura 2-loaded Chinese hamster ovary cells expressing the bovine cardiac Na+/Ca2+ exchanger (NCX1.1). La3+ was taken up by the cells after an initial lag phase of 50-60 s and achieved a steady state within 5-6 min. Neonatal cardiac myocytes accumulated La3+ in a similar manner. La3+ uptake was due to the activity of the exchanger, because no uptake was seen in nontransfected cells or in transfected cells that had been treated with gramicidin to remove cytosolic Na+. The low rate of La3+ uptake during the lag period resulted from insufficient cytosolic Ca2+ to activate the exchanger at its regulatory sites, as shown by the following observations. La3+ uptake occurred without a lag period in cells expressing a mutant of NCX1.1 that does not exhibit regulatory activation by cytosolic Ca2+. The rate of La3+ uptake by wild-type cells was increased, and the lag phase was reduced or eliminated, when the cytosolic Ca2+ concentration was increased before initiating La3+ uptake. La3+ could substitute for Ca2+ at very low concentrations to activate exchange activity. Thus preloading cells expressing NCX1.1 with a small quantity of La3+ increased the rate of exchange-mediated Ca2+ influx by 20-fold; in contrast, cytosolic La3+ partially inhibited Ca2+ uptake by the regulation-deficient mutant. With an estimated KD of 30 pM for the binding of La3+ to fura 2, we conclude that cytosolic La3+ activates exchange activity at picomolar concentrations. We speculatively suggest that endogenous trace metals might activate exchange activity under physiological conditions.