AbstractSynaptic transmission involves Ca2+ influx at presynaptic terminals. Adenosine receptors inhibit transmission, and this effect can be abolished by activation of PKC with phorbol esters. Whether protein kinase C (PKC) acts via alterations in Ca2+ entry at the presynaptic terminal is unknown. In the present study, we recorded the presynaptic Ca2+ transients (preCaΔ) in hippocampal stratum radiatum, using fluorescence photometry. The calcium dye Fura‐2 AM was used to load the Schaffer collateral/commissural tract and its terminals. Tetrodotoxin (TTX)‐sensitive Na+ channels and Cd2+‐sensitive, high‐voltage activated Ca2+ channels (HVACCs) were required to elicit the preCaΔ. Application of the phorbol ester phorbol‐12,13‐dibutyrate (PDBu) abolished the adenosine inhibition of both preCaΔ and the field excitatory postsynaptic potentials (fEPSPs). PDBu consistently potentiated fEPSPs, and also increased preCaΔ in a large majority of the slices examined. Regardless of whether potentiation was observed, PDBu always prevented adenosine inhibition of preCaΔ. In contrast, the inactive phorbol ester, 4α‐phorbol, did not alter adenosine inhibition of preCaΔ, indicating that PKC activation is necessary for the occurrence of the observed effects. Our findings suggest that PKC activation abolishes adenosine's inhibitory effect on synaptic activity involving presynaptic Ca2+ entry. Hippocampus 2003;13:355–360. © 2003 Wiley‐Liss, Inc.