ADENINE DINUCLEOTIDES - A NOVEL CLASS OF SIGNALING MOLECULES

1 Adenine dinucleotides (Ap3A, Ap4A, Ap5A, Ap6A) are stored in secreto ry granules of thrombocytes, chromaffin cells and neuronal cells. Afte r release into the extracellular space, the dinucleotides exhibit dive rgent biological effects on a variety of target cells and organs. The dinucleotides are metabolized by soluble enzymes in the blood plasma a s well as by membrane-bound ectoenzymes of endothelial cells, smooth m uscle cells, and other cell types. 2 The enzymatic cleavage of the din ucleotides plays a dual role for their biological function: (a) termin ation of the signal; and (b) generation of purinergically active produ cts such as ATP, ADP and finally adenosine. In contrast to ATP the din ucleotides are long-lived purine nucleotides in the blood. 3 The poten tial role of the dinucleotides as signalling molecules has been demons trated in several systems. The adenosine polyphosphates have autocrine function for thrombocytes. Ap3A at low concentration reversibly activ ates isolated platelets. The mechanism of activation has been elucidat ed by showing a continuous cleavage of Ap3A, leading to the formation of ADP which is a known agonist of the P2T receptor an thrombocytes. A p4A and other dinucleotides act as antagonists and inhibit platelet ac tivation. 4 The vasotone of perfused isolated arteries as well as of r esistance vessels in the beating heart is differentially influenced by adenine dinucleotides. While Ap3A and Ap4A exhibit relaxing effects a t micromolar concentrations, Ap5A and Ap6A elicit vasoconstriction in these vessels. 5 In rat kidney mesangial cells adenine dinucleotides e fficiently promote growth. Stimulation of DNA synthesis by various gro wth factors is enhanced synergistically. ApnA significantly increase t he expression of the early growth response gene Egr-1. 6 The specifici ty and, in some tissues, the uniqueness of effects evoked by dinucleot ides may be mediated by genuine dinucleotide receptors (P4) or by spec ialized P2 receptors (P2D).