Purinergic signalling and disorders of the central nervous system

Key Points

  • Adenosine-5′-triphosphate (ATP) is the transmitter responsible for non-adrenergic, non-cholinergic neuromuscular transmission; the purinergic signalling hypothesis was proposed in 1972.

  • Receptor subtypes for purines and pyrimidines were cloned and characterized, and four P1(adenosine), seven P2X ion channels and eight P2Y G protein-coupled receptors have been identified.

  • ATP and adenosine regulate the release of glutamate, g-aminobutyric acid, acetylcholine and dopamine.

  • ATP, which is released as a cotransmitter from neurons and astrocytes in the brain, and its breakdown product adenosine are involved in learning and memory, locomotion, feeding and sleep.

  • Purinergic signalling has important roles in various pathophysiological conditions of the central nervous system (CNS) including: trauma, ischaemia, neurodegenerative diseases (including Parkinson's, Alzheimer's and Huntington's disease and amyotrophic lateral sclerosis), neuroimmune and inflammatory diseases (including multiple sclerosis), epilepsy and neuropsychiatric disorders (including depression and anxiety, schizophrenia, alcohol and drug addiction) and neuropathic pain (including migraine).

  • P2X1, P2X4, P2X7, P2Y6 and P2Y12 receptors are expressed by microglia, which are immune cells in the CNS, and appear to have a major role in a number of disease conditions.

  • Therapeutic strategies involving purinergic compounds are being developed for these diseases, in particular: A2A receptor antagonists for Parkinson's disease; P2X7 receptor antagonists for brain damage following trauma, inflammation and neuropathic pain; P2X3, P2X2/3 and P2X4 receptor antagonists are being targeted for chronic pain; P2Y1 receptor agonists for multiple sclerosis; A1 agonists and A2A and P2X7 antagonists for epileptic seizures and A1 and A2A receptor agonists for mood disorders.

  • Although there is compelling evidence that purinergic signalling has an important role in CNS diseases, the use of purinergic agents is not yet in the clinic and is limited by the lack of selective agents that are orally bioavailable, cross the blood–brain barrier and are stable in vivo.

Abstract

Purines have key roles in neurotransmission and neuromodulation, with their effects being mediated by the purine and pyrimidine receptor subfamilies, P1, P2X and P2Y. Recently, purinergic mechanisms and specific receptor subtypes have been shown to be involved in various pathological conditions including brain trauma and ischaemia, neurodegenerative diseases involving neuroimmune and neuroinflammatory reactions, as well as in neuropsychiatric diseases, including depression and schizophrenia. This article reviews the role of purinergic signalling in CNS disorders, highlighting specific purinergic receptor subtypes, most notably A2A, P2X4 and P2X7, that might be therapeutically targeted for the treatment of these conditions.

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Figure 1: Purinergic signalling in the spinal cord.
Figure 2: Hypothetical schematic of the roles of purine nucleotides and nucleosides in pain pathways.

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Acknowledgements

I thank G. E. Knight for her excellent editorial assistance.

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Supplementary information S1 (figure)

Microglia activation by ATP (PDF 190 kb)

Supplementary information S2 (table)

Functional pharmacological evaluation of P2X7 antagonists (PDF 105 kb)

Supplementary information S3 (box)

Abbreviations for tables 2 and 3 (PDF 122 kb)

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Burnstock, G. Purinergic signalling and disorders of the central nervous system. Nat Rev Drug Discov 7, 575–590 (2008). https://doi.org/10.1038/nrd2605

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