, Volume 452, Issue 5, pp 563-572
Date: 11 May 2006

Dinucleoside polyphosphates and their interaction with other nucleotide signaling pathways

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Dinucleoside polyphosphates or ApnA are a family of dinucleotides formed by two adenosines joined by a variable number of phosphates. Ap4A, Ap5A, and Ap6A are stored together with other neurotransmitters into secretory vesicles and are co-released to the extracellular medium upon stimulation. These compounds can interact extracellularly with some ATP receptors, both metabotropic (P2Y) and ionotropic (P2X). However, specific receptors for these substances, other than ATP receptors, have been described in presynaptic terminals form rat midbrain. These specific dinucleotide receptors are of ionotropic nature and their activation induces calcium entry into the terminals and the subsequent neurotransmitter release. Calcium signals that cannot be attributable to the interaction of ApnA with ATP receptors have also been described in cerebellar synaptosomes and granule cell neurons in culture, where Ap5A induces CaMKII activation. In addition, cerebellar astrocytes express a specific Ap5A receptor coupled to ERK activation. Ap5A engaged to MAPK cascade by a mechanism that was insensitive to pertussis toxin and required the involvement of src and ras proteins. Diadenosine polyphosphates, acting on their specific receptors and/or ATP receptors, can also interact with other neurotransmitter systems. This broad range of actions and interactions open a promising perspective for some relevant physiological roles for the dinucleotides. However, the physiological significance of these compounds in the CNS is still to be determined.