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Pathological Potential of Astroglial Purinergic Receptors

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Glutamate and ATP at the Interface of Metabolism and Signaling in the Brain

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 11))

Abstract

Acute brain injury and neurodegenerative disorders may result in astroglial activation. Astrocytes are able to determine the progression and outcome of these neuropathologies in a beneficial or detrimental way. Nucleotides, e.g. adenosine 5′-triphosphate (ATP), released after acute or chronic neuronal injury, are important mediators of glial activation and astrogliosis.

Acute injury may cause significant changes in ATP balance, resulting in (1) a decline of intracellular ATP levels and (2) an increase in extracellular ATP concentrations via efflux from the intracellular space. The released ATP may have trophic effects, but can also act as a proinflammatory mediator or cytotoxic factor, inducing necrosis/apoptosis as a universal “danger” signal. Furthermore, ATP, primarily released from astrocytes, is a means of communication between neurons, glial cells, and intracerebral blood vessels.

Astrocytes express a heterogeneous battery of purinergic ionotropic and metabotropic receptors (P2XRs and P2YRs, respectively) to respond to extracellular nucleotides.

In this chapter, we summarize the contemporary knowledge on the pathological potential of P2Rs in relation to changes of astrocytic functions, determined by distinct molecular signaling cascades, in a variety of diseases. We discuss specific aspects of reactive astrogliosis, with respect to the involvement of prominent receptor subtypes, such as the P2X7 and P2Y1/2Rs. Examples of purinergic signaling of microglia, oligodendrocytes, and blood vessels under pathophysiological conditions will also be presented.

The understanding of the pathological potential of purinergic signaling in “controlling and fine-tuning” of astrocytic responses is important for identifying possible therapeutic principles to treat acute and chronic central nervous system diseases.

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Abbreviations

AD:

Alzheimer’s disease

AKT:

Serine-threonine kinase AKT

ALS:

Amyotrophic lateral sclerosis

AP-1:

Activator protein-1

AQP-4:

Aquaporin-4

ATP:

Adenosine 5′-triphosphate

BBB:

Blood-brain barrier

[Ca2+]i :

Intracellular free calcium concentration

CNS:

Central nervous system

COX:

Cyclooxygenase

EAE:

Experimental autoimmune encephalomyelitis

ERK:

Extracellular signal-regulated protein kinase

GFAP:

Glial fibrillary acidic protein

GSK-3:

Glycogen synthase kinase-3

IL:

Interleukin

InsP3 :

Inositol-(1,4,5)-trisphosphate

IR:

Immunoreactivity

JNK:

Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MCAO:

Middle cerebral artery occlusion

NF-κB:

Nuclear factor-κB

NG2:

Chondroitin sulfate proteoglycan

OPC:

Oligodendrocyte precursor cells

P2R:

Purinergic receptor

PD:

Parkinson’s disease

PI3K:

Phosphatidylinositol 3-kinase

PKC:

Protein kinase C

SAPK:

Stress-activated protein kinase

SCI:

Spinal cord injury

STAT3:

Signal transducer and activator of transcription 3

TBI:

Traumatic brain injury

TNF:

Tumor necrosis factor

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (FR 1253/3-1; IL 20/18-2).

Conflict of interest The authors declare no conflict of interest.

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  1. Rudolf Boehm Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstraße 16-18, 04107, Leipzig, Germany

    Heike Franke & Peter Illes

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  1. Heike Franke
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  2. Peter Illes
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Correspondence to Heike Franke .

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  1. Department of Neurobiology CIRC 429, University of Alabama, Birmingham, Alabama, USA

    Vladimir Parpura

  2. Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Arne Schousboe

  3. Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom

    Alexei Verkhratsky

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Franke, H., Illes, P. (2014). Pathological Potential of Astroglial Purinergic Receptors. In: Parpura, V., Schousboe, A., Verkhratsky, A. (eds) Glutamate and ATP at the Interface of Metabolism and Signaling in the Brain. Advances in Neurobiology, vol 11. Springer, Cham. https://doi.org/10.1007/978-3-319-08894-5_11

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