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Pathophysiology of astroglial purinergic signalling

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Abstract

Astrocytes are fundamental for central nervous system (CNS) physiology and are the fulcrum of neurological diseases. Astroglial cells control development of the nervous system, regulate synaptogenesis, maturation, maintenance and plasticity of synapses and are central for nervous system homeostasis. Astroglial reactions determine progression and outcome of many neuropathologies and are critical for regeneration and remodelling of neural circuits following trauma, stroke, ischaemia or neurodegenerative disorders. They secrete multiple neurotransmitters and neurohormones to communicate with neurones, microglia and the vascular walls of capillaries. Signalling through release of ATP is the most widespread mean of communication between astrocytes and other types of neural cells. ATP serves as a fast excitatory neurotransmitter and has pronounced long-term (trophic) roles in cell proliferation, growth, and development. During pathology, ATP is released from damaged cells and acts both as a cytotoxic factor and a proinflammatory mediator, being a universal “danger” signal. In this review, we summarise contemporary knowledge on the role of purinergic receptors (P2Rs) in a variety of diseases in relation to changes of astrocytic functions and nucleotide signalling. We have focussed on the role of the ionotropic P2X and metabotropic P2YRs working alone or in concert to modify the release of neurotransmitters, to activate signalling cascades and to change the expression levels of ion channels and protein kinases. All these effects are of great importance for the initiation, progression and maintenance of astrogliosis–the conserved and ubiquitous glial defensive reaction to CNS pathologies. We highlighted specific aspects of reactive astrogliosis, especially with respect to the involvement of the P2X7 and P2Y1R subtypes. Reactive astrogliosis exerts both beneficial and detrimental effects in a context-specific manner determined by distinct molecular signalling cascades. Understanding the role of purinergic signalling in astrocytes is critical to identifying new therapeutic principles to treat acute and chronic neurological diseases.

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Abbreviations

AA:

Arachidonic acid

Aβ:

Oligomeric β-amyloid peptide

AC:

Adenylate cyclase

AD:

Alzheimer’s disease

AKT:

Serine-threonine kinase AKT

ALS:

Amyotrophic lateral sclerosis

APP:

Amyloid precursor protein

ATP:

Adenosine 5′-triphosphate

BrdU:

5-Bromo-2′-deoxyuridine

[Ca2+]i :

Intracellular free calcium concentration

cAMP:

Cyclic adenosine-3′,5′-monophosphate

cGMP:

Cyclic guanosine-3′,5′-monophosphate

CNS:

Central nervous system

COX:

Cyclooxygenase

DAG:

Diacylglycerol

DRG:

Dorsal root ganglion

EGF:

Epidermal growth factor

EGFP:

Enhanced green fluorescent protein

ERK:

Extracellular signal regulated protein kinase

FGF:

Fibroblast growth factor

GFAP:

Glial fibrillary acidic protein

GSK3:

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

MS:

Multiple sclerosis

NAc:

Nucleus accumbens

NGF:

Nerve growth factor

NG2:

Chondroitin sulphate proteoglycan

NF-κB:

Nuclear factor-κB

NO:

Nitric oxide

PD:

Parkinson’s disease

PDGF:

Platelet-derived growth factor

PGE2 :

Prostaglandin E2

PKC:

Protein kinase C

PI3K:

Phosphatidylinositol 3-kinase

PL(A2):

Phospholipase (A2)

PPADS:

Pyridoxal-phosphate-6-azophenyl-2′,4′-disulphonic acid

P2R:

Purinergic receptor

SAPK:

Stress-activated protein kinase

SE:

Status epilepticus

STAT3:

Signal transducer and activator of transcription 3

TBI:

Traumatic brain injury

TNF:

Tumor necrosis factor

UTP:

Uridine 5′-triphosphate

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Acknowledgments

The authors thank Katrin Becker, Helga Sobottka, Katrin Krause and Lutz Feige for excellent technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (FR 1253/3-2).

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Authors and Affiliations

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

    Heike Franke & Peter Illes

  2. Faculty of Life Sciences, The University of Manchester, Manchester, M13 9PT, UK

    Alexei Verkhratsky

  3. Autonomic Neuroscience Centre, Royal Free and University College Medical School, London, NW3 2PF, UK

    Geoffrey Burnstock

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  1. Heike Franke
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  2. Alexei Verkhratsky
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  3. Geoffrey Burnstock
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  4. Peter Illes
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Correspondence to Heike Franke.

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Franke, H., Verkhratsky, A., Burnstock, G. et al. Pathophysiology of astroglial purinergic signalling. Purinergic Signalling 8, 629–657 (2012). https://doi.org/10.1007/s11302-012-9300-0

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