Pathophysiology and Therapeutic Potential of Purinergic Signaling
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Geoffrey Burnstock
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Autonomic Neuroscience Centre, Royal Free and University College Medical School, London, United Kingdom
Abstract
The concept of a purinergic signaling system, using purine nucleotides and nucleosides as extracellular messengers, was first proposed over 30 years ago. After a brief introduction and update of purinoceptor subtypes, this article focuses on the diverse pathophysiological roles of purines and pyrimidines as signaling molecules. These molecules mediate short-term (acute) signaling functions in neurotransmission, mechanosensory transduction, secretion and vasodilatation, and long-term (chronic) signaling functions in cell proliferation, differentiation, and death involved in development and regeneration. Plasticity of purinoceptor expression in pathological conditions is frequently observed, including an increase in the purinergic component of autonomic cotransmission. Recent advances in therapies using purinergic-related drugs in a wide range of pathological conditions will be addressed with speculation on future developments in the field.
I. Introduction
A seminal article by Drury and Szent-Gyrgi in 1929 described the potent actions of purine nucleotides and nucleosides, ATP, and adenosine on the heart and blood vessels. Then, in 1970, evidence was presented for ATP as a neurotransmitter in nonadrenergic, noncholinergic (NANC1) nerves supplying the gut (Burnstock et al., 1970) and in 1972 the word "purinergic" was coined and the purinergic neurotransmission hypothesis was proposed by Burnstock (Burnstock, 1972). This concept met with considerable resistance for many years, because ATP had been established as an intracellular energy source involved in various metabolic cycles, and it was thought that such a ubiquitous molecule was unlikely to be involved in selective extracellular signaling. However, the concept is now widely accepted. Later, it was established that ATP was a cotransmitter with classic 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, musculoskeletal, immune, and inflammatory cells (Burnstock and Knight, 2004).
Implicit in the purinergic hypothesis was the presence of purinoceptors (Ralevic and Burnstock, 1998). 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, whereas others were due to indirect action via P1 receptors. Four subtypes of P1 receptors were cloned, namely, A1, A2A, A2B, and A3. 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 (Fredholm et al ......
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