Title

 

Authors

C. Volonté, S. Amadio, S. Apolloni, C. Parisi, N. D’Ambrosi
 
CNR-IBCN/Fondazione Santa Lucia
Via Del Fosso di Fiorano 65, 00143 Rome, IT

 

Abstract

Ectonucleotidases, P2 receptors for purine/pyrimidine nucleotides, P1 receptors for nucleosides, in addition to ATP/adenosine transporters, rarely operate as single units. They associate with each other within multiprotein complexes and intermolecular networks that overall determine the magnitude and/or direction of the signals triggered and propagated by the ligands. The insurgence, duration and termination of the purinergic/pyrimidinergic signalling is then ruled by the space-time coincidence of these interactions at the plasma membrane. These generally occur in specialized sub-membrane compartments such as lipid rafts, rafts-like structures and caveolae that behave as complex control systems. Indeed, compartments dynamically exclude or include proteins, separate unrelated reactions, favour proper cooperative behaviour in response to particular physiopathological requirements. Highly sophisticated cellular heterogeneity is thus generated, together with modelling of the cell architecture and biochemistry. Within the P2X sub-family, endocytic trafficking studies have shown for instance how P2X₁ receptor can internalize and recycle back to the plasma membrane in response to agonist application. On the other hand, the P2X₄ subtype constitutively internalizes and recycles at high rates, while its surface expression can be directly regulated by exocytosis from lysosomes. Also the P2X₃ receptor subtype shows rapid constitutive endocytosis and targeting to the late endosomal/lysosomal system, with overall localization in these organelles at steady-state and consequent high degradation rates. Within the P2Y sub-family, ligand-induced internalization and endocytic trafficking have been extensively studied for P2Y₁ and P2Y₂ receptors. Although the implications for receptor functional regulation in vivo are still premature, these findings describing highly dynamic trafficking of P2 receptors certainly disclose a possible mechanism for the rapid modulation of ATP-mediated responses potentially relevant during physiological as well as pathological conditions.