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From the very early evolution of life purines have acquired the meaning of damage-associated extracellular signaller and purinergic receptors emerged in unicellular organisms. Ancestral purinoceptors are P2X-like ionotropic ligand-gated cationic channels showing 20–40% of homology with vertebrate P2X receptors; genes encoding ancestral P2X receptors have been detected in Protozoa, Algae, Fungi and Sponges; they are also present in some invertebrates, but are absent from the genome of insects, nematodes, and higher plants. Plants nevertheless evolved a sophisticated and widespread purinergic signalling system relying on the idiosyncratic purinoceptor P2K1/DORN1 linked to intracellular Ca2+ signalling. The advance of metabotropic purinoceptors starts later in evolution with adenosine receptors preceding the emergence of P2Y nucleotide and P0 adenine receptors. 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