Membrane compartments and purinergic signalling: the purinome, a complex interplay among ligands, degrading enzymes, receptors and transporters

Abstract

Receptors should be properly analysed in view of the microenvironment in which they are embedded. Therefore, the concept of 'receptosome' was formulated to the complex interactions taking place between receptors and other proteins at the plasma membrane level, and to explain very heterogeneous or divergent cellular responses to common epigenetic factors and modifications to the extracellular environment. The receptosome thus becomes a molecular network connecting transmitters, hormones or growth factors, to both their specific receptors and unique downstream effector proteins. As an example of receptosome, we introduce here the 'purinome' as molecular complex responsible for the biological effects of extracellular purine and pyrimidine ligands. In addition to a vast heterogeneity of purinergic ligands, the purinome thus consists of ectonucleotide-metabolizing enzymes hydrolysing nucleoside phosphates, purinergic receptors classified as P1 for adenosine/AMP and P2 for nucleosides tri-/diphosphates, nucleoside transporters with both equilibrative and concentrative properties and finally, nucleotide channels and transporters. Notably, these purinergic elements are not independent, but they play tightly concerted actions under physiological conditions. As a whole and not singularly, they trigger, maintain and terminate the purinergic signalling. This signifies that the purinome is not a new, mere definition of juxtaposed purinergic units, but rather the experimental evidence of complex and dynamic molecular cross-talk and cooperation networks. Alteration of this dynamic equilibrium may even participate in many pathological states. As a consequence, to be successful against pathological conditions, the genetic/pharmacological manipulation of purinergic mechanisms must go well beyond single proteins, and be more holistically oriented.