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VOL. 71 (2), 283-319, 2005 PURINERGIC SIGNALLING: THERAPEUTIC POTENTIAL

was established that ATP was a cotransmitter with classical
transmitters in both the peripheral and central nervous systems, and
that purines are also powerful extracellular messengers to non-
neuronal cells, including exocrine and endocrine, secretory,
endothelial, bone, immune and inflammatory cells (1).

Implicit in the purinergic hypothesis was the presence of
purinoceptors (2). A basis for distinguishing P1 (adenosine) from
P2 (ATP/ADP) receptors was proposed by Burnstock in 1978. This
helped resolve some of the ambiguities in earlier reports, which
were complicated by the breakdown of ATP to adenosine by
ectoenzymes so that some of the actions of ATP were directly on
P2 receptors, while others were due to indirect action via P1 receptors.
Four subtypes of P1 receptors were cloned, namely A1, A2A, A2B and
A3 and in 1985, Burnstock and Kennedy proposed a basis for
distinguishing two types of P2 purinoceptor, namely P2X and P2Y,
based largely on pharmacological criteria. In the early 1990s, studies
of transduction mechanisms and cloning of both P2X and P2Y
receptors were carried out, which led Abbracchio and Burnstock to
put forward a new nomenclature system in 1994, which is now widely
accepted. They proposed that there were two families of P2
purinoceptors, namely P2X ionotropic ligand-gated ion channel
receptors and P2Y metabotropic G protein-coupled receptors. This
framework has allowed a logical expansion as new receptors were
identified. Currently seven subtypes of P2X receptors and eight
subtypes of P2Y receptors are clearly recognized and their distribution
in the body and pharmacological properties have been defined. The
P2X1 receptor is prominent in contractile smooth muscle cells, but is
not detectable in proliferating smooth muscle cells, in which P2Y
receptor expression is substantially increased.

Purinergic signalling is rapid in synaptic neurotransmission,
neuromuscular transmission leading to contraction or relaxation of
smooth muscle and in exocrine or endocrine secretion. However,
there are now many examples of purinergic signalling regulating
long-term events such as cell proliferation, differentiation, migration
and death in development, regeneration and wound healing. Both
P2X and P2Y receptors play prominent roles in embryonic
development, including the nervous system, cartilage in limb buds,
the mesonephros, retina, myotubes and neuromuscular junctions.

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