Liver cells possess multiple types of purinoceptors that mediate the effects of extracellular nucleotides. Like ADP and ATP, the dinucleotides diadenosine triphosphate (Ap3A) and diadenosine tetraphosphate (Ap4A) fully activated glycogen phosphorylase, with ED50 values of 0.31 microM and 1.3 microM, respectively. At variance with ATP, neither the dinucleotides nor ADP significantly increased the levels of IP3.Ap4A (and also ADP) moderately increased IP3 (+/- 72%) whereas Ap3A was completely ineffective. Like ATP, Ap3A, Ap4A, and ADP inhibited the cAMP increase after glucagon. Phorbol-12-myristate-13-acetate (PMA) pretreatment of the hepatocytes clearly inhibited the glycogenolytic potency of Ap3A and ADP, but had only a minor effect on the potency of Ap4A or ATP. It is concluded that, depending upon the effect studied (glycogenolytic effect with or without PMA, increasing IP3 potency, or inhibition of cAMP increase), different analogies between the agonists studied emerged, indicating the complexity of the interaction of ATP and its analogues with liver purinoceptors and/or of the transduction mechanism(s) initiated by the different nucleotides.