La3+ stimulate the activity of calcineurin in two different ways

It is well known that the activity of calcineurin (CaN) could be modulated by several transitional metal ions. In the present work, the effects of a calcium analog, lanthanum ion (La(3+)), on the activity of CaN were studied. It was found that La(3+) exerted multiple effects on CaN activity. La(3+) could stimulate CaN in the absence of calmodulin (CaM); whereas at low concentrations of La(3+), there was a slight inhibition of activation of CaN in the presence of CaM. Competitive experiments and limited trypsin proteolysis confirmed that La(3+) did not act on the catalytic core of CaN, but exerted its effect through direct action on the CaN regulatory domain similar to Mg(2+). In activity titration and spot blotting studies, La(3+)-containing CaM complexes were less effective in stimulating CaN than Ca(2+) or Mn(2+)-containing CaM; however, the binding affinity of these metal-CaM complexes to CaN was similar. These effects of La(3+) on CaN activity are unique among metal ions and may provide clues to understand the biological effects of La(3+).