Ca2*-regulated protein kinases play critical roles in long-term potentiation (LTP). To understand the role of Ca2*/calmodulin (CAM) signaling pathways in synaptic transmission better, Ca2÷ ICaM was injected into hippocampal CA1 neurons. Ca=*/CaM induced significant potentiation of excitatory synaptic responses, which was blocked by coinjection of a CaM-binding peptide and was not induced by injections of Ca 2+ or CaM alone. Reciprocal experiments demonstrated that Ca2*/CaM-induced synaptic potentiation and tetanusinduced LTP occluded one another. Pseudosubatrate inhibitors or high-affinity substrates of CaMKII or PKC blocked Ca=* lCaM-induced potentiation, indicating the requirement of CaMKII and PKC activities in synaptic potentiation. We suggest that postsynaptic levels of free Ca=+ ICaM is a rate limiting factor and that functional cross-talk between Ca=*/CaM and PKC pathways occurs during the induction of LTP.