Although lanthanide ions La3+ and Tb3+ were only slightly able to substitute for Ca2+ to activate phospholipid-sensitive Ca2+-dependent protein kinase (PL-Ca-PK), they potentiated the ability of a ...suboptimal concentration of Ca2+ to stimulate the enzyme. In comparison, the lanthanides were more effective Ca2+ substitutes for myosin light chain kinase, a calmodulin-sensitive Ca2+-dependent protein kinase. Both enzymes, however, were inhibited by high concentrations of lanthanides either in the presence or absence of Ca2+. Similar effects of the lanthanides were also noted on phosphorylation of endogenous substrates in the particulate fraction of rat brain stimulated by either phosphatidylserine/Ca2+ or calmodulin/Ca2+. The La3+- or Tb3+-stimulated activity of PL-Ca-PK, as the Ca2+-stimulated activity, was inhibited by various agents, such as trifluoperazine, polymyxin B, cobra cytotoxin I, melittin, and spermine.