Pathophysiology of astroglial purinergic signalling;...Heike Frankie/Springer.Pub.

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.

Keywords  Astroglia – Astrogliosis – ATP – P2X/Y receptors – Neurodegeneration – Pathophysiology – Purinergic signalling

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