The uptake of Ca2+ by a K+-depolarized rat brain cerebral cortical crude synaptosomal preparation (P2 fraction) was investigated. The characteristics of the Ca2+ uptake system are similar to those observed by other investigators. The preparation is also a suitable model with which to study the effects of adenosine on Ca2+ uptake and neurotransmitter release, as it is generally accepted that K+-evoked Ca2+ uptake is intimately related to depolarization-induced release of neurotransmitters. We have demonstrated that an extracellular receptor is involved in mediating the adenosine-evoked inhibition of K+-evoked Ca2+ uptake. The pharmacological properties of the receptor suggest that it may be similar in some respects to the A2-receptor associated with adenylate cyclase. The adenosine uptake inhibitor, dipyridamole, potentiated the action of adenosine, suggesting that re-uptake is important in controlling the extracellular adenosine concentration and thus in the regulation of the adenosine receptor. The adenosine receptor antagonist theophylline inhibited the effects of adenosine. Calmodulin inhibited K+-evoked uptake of Ca2+ by the synaptosomal fraction.