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Purinergic signalling in neuron–glia interactions

Key Points

  • Activity-dependent release of ATP from neurons and glia activates a large family of membrane receptors that allow glia to detect synaptic and action potential activity and communicate among other glial cells. Purinergic signalling regulates glial cell proliferation, motility, survival, differentiation and myelination in response to neural impulse activity. In turn, purinergic signalling allows glia to regulate synaptic transmission, excitability and responses to nervous system injury and disease.

  • All major types of glia and most neurons have functional purinergic receptors. These belong to a large family of membrane receptors that are activated by ATP and its breakdown products, ADP, AMP and adenosine. These are broadly divided into P1 and P2 receptors, which are activated preferentially by adenosine and ATP, respectively.

  • These receptors signal through intracellular calcium and cyclic AMP pathways. The receptor family includes both calcium-permeable ion channels and G-protein-coupled receptors.

  • Functional implications of purinergic signalling in the nervous system include neuron–glia communication, differentiation of stem cells, nervous system disease and response to injury, neurovascular and neuroimmune interactions, synaptic transmission and plasticity, glial differentiation, intercellular communication among glia, and myelination.

  • ATP is released from neurons and glia by several mechanisms, including from membrane vesicles and through channels. Glia can detect the activity-dependent release of ATP from neurons, and the release of ATP from glia mediates intercellular signalling between astrocytes, oligodendrocytes and microglia.

  • Perisynaptic glia detect ATP released from synapses, and, in turn, release neurotransmitters, neuromodulators, ATP or adenosine to influence synaptic transmission in the hippocampus, neuromuscular junction, retina and other regions. ATP and adenosine released by neurons and glia participate in long-term potentiation and long-term depression in the hippocampus.

  • Myelinating glia in the PNS and CNS detect ATP released from axons. Impulse activity stimulates myelination by oligodendrocytes and inhibits myelination by Schwann cells.

  • Purinergic signalling interacts with cytokine and growth factor signalling. This broadens the biological functions regulated by purinergic signalling, and engages cytokine and growth factor signalling according to neural impulse activity.

  • The hydrolysis of extracellular ATP is controlled by ectoenzymes, which are spatially and developmentally regulated.

  • Microglial involvement in chronic pain and response to injury are mediated, in part, by purinergic signalling.

Abstract

Activity-dependent release of ATP from synapses, axons and glia activates purinergic membrane receptors that modulate intracellular calcium and cyclic AMP. This enables glia to detect neural activity and communicate among other glial cells by releasing ATP through membrane channels and vesicles. Through purinergic signalling, impulse activity regulates glial proliferation, motility, survival, differentiation and myelination, and facilitates interactions between neurons, and vascular and immune system cells. Interactions among purinergic, growth factor and cytokine signalling regulate synaptic strength, development and responses to injury. We review the involvement of ATP and adenosine receptors in neuron–glia signalling, including the release and hydrolysis of ATP, how the receptors signal, the pharmacological tools used to study them, and their functional significance.

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Figure 1: Purinergic receptors bind extracellular ATP and the reaction products that result from its enzymatic hydrolysis by ectonucleotidases.
Figure 2: Membrane receptors for extracellular ATP and adenosine.
Figure 3: Astrocytes have several types of ionotropic and metabotropic membrane receptor for ATP and its breakdown products, ADP, AMP and adenosine, which increase intracellular calcium concentrations.
Figure 4: Calcium imaging reveals that glial cells can respond to electrical activity in axons.

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Acknowledgements

Supported in part by The National Institute of Child Health and Human Development, National Institutes of Health intramural research funds.

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Supplementary information

Supplementary information S1 (movie)

Activity-dependent communication between axons and astrocytes. Confocal calcium imaging in cell culture reveals communication among mouse astrocytes through waves of intracellular calcium, as well as responses of astrocytes to action potentials in axons. The calcium waves are mediated in part by the release of ATP from astrocytes acting on purinergic receptors of other cells to stimulate a rise in intracellular calcium concentration. Action potentials stimulated in DRG axons, which are shown as bright light passing horizontally through the image, release ATP from non-synaptic regions as well as from synapses, although there are no synapses in these cultures. ATP released from axons is detected by purinergic receptors on astrocytes, allowing action potentials to stimulate waves of calcium among astrocytes. In addition to ATP, other neurotransmitters and intercellular signalling molecules participate in activity-dependent axon-glial signalling. The time-lapse movie compresses 15 mins of activity. See FIG. 4 for further description. (MOV 977 kb)

Supplementary information S2 (table) (PDF 37 kb)

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FURTHER INFORMATION

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Glossary

Tetanus toxin

Protein derived from Clostridium tetani that can block transmitter release owing to its ability to degrade synaptobrevin. Tetanus toxin is the causative agent of tetanus.

Adenylyl cyclase

An enzyme that synthesizes cAMP, a second messenger molecule that relays signals received from receptors on the cell surface to intracellular signalling pathways.

Diadenosine polyphosphate

A phosphorylated form of adenosine dinucleotide, which is released from neurosecretory vesicles together with ATP.

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Fields, R., Burnstock, G. Purinergic signalling in neuron–glia interactions. Nat Rev Neurosci 7, 423–436 (2006). https://doi.org/10.1038/nrn1928

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