The roles of P-2X1 and P-2TAC receptors in ADP-evoked Ca2+ signalling were investigated in fura-2-loaded human platelets. Desensitization of the P-2X1, receptor with the selective agonist, alpha beta-methylene ATP, reduced the integral of the ADP-evoked rise in [Ca2+](i) to about 90% of control; a reduction equivalent to the integral of the P-2X1-evoked response alone. After elevating cAMP or cGMP levels using prostaglandin E-1 or sodium nitroprusside, prior P-2X1 desensitization reduced the integral of the ADP-evoked response to about 70% of control. This reduction was greater than the integral of the P-2X1-evoked response alone under the same conditions, suggesting rapidly activated Ca2+ entry via the P-2X1 receptor potentiates Ca2+ responses evoked via the phospholipase C-coupled P-2Y1 receptor. The P-2TAC receptor antagonist, AR-C69931MX, at a concentration completely inhibiting aggregation, did not significantly affect the initial peaks but caused a significant reduction in the integrals of the ADP-evoked rises in [Ca2+](i) to about 71% or 77% of controls in the presence or absence of external Ca2+ respectively. This suggests that the main effect of lowering cAMP levels after inhibition of adenylyl cyclase via P-2TAC receptors may be reduced Ca2+ removal from the cytosol. These results indicate that both the P-2X1 and P-2TAC receptors play a significant role in ADP-evoked Ca2+ signalling in human platelets.