Modulation of the phosphorylation and activity of calcium/calmodulin-dependent protein kinase II by zinc

Calcium/calmodulin-dependent protein kinase II (CaMPK-II) is a key regulato ry enzyme in living cells. Modulation of its activity, therefore, could hav e a major impact on many cellular processes. We found that Zn2+ has multipl e functional effects on CaMPK-II. Zn2+ generated a Ca2+/CaM-independent act ivity that correlated with the autophosphorylation of Thr(286), inhibited C a2+/ CaM binding that correlated with the autophosphorylation of Thr(306), and inhibited CaMPK-II activity at high concentrations that correlated with the autophosphorylation of Ser(279). The relative level of autophosphoryla tion of these three sites was dependent on the concentration of zinc used. The autophosphorylation of at least these three sites, together with Zn2+ b inding, generated an increased mobility form of CaMPK-II on sodium dodecyl sulfate gels. Overall, autophosphorylation induced by Zn2+ converts CaMPK-I I into a different form than the binding of Ca2+/CaM. In certain nerve term inals, where Zn2+ has been shown to play a neuromodulatory role and is pres ent in high concentrations, Zn2+ may turn CaMPK-II into a form that would b e unable to respond to calcium signals.