Roles of P2 receptors in glial cells: focus on astrocytes

Abstract

Central nervous system glial cells release and respond to nucleotides under both physiological and pathological conditions, suggesting that these molecules play key roles in both normal brain function and in repair after damage. In particular, ATP released from astrocytes activates P2 receptors on astrocytes and other brain cells, allowing a form of homotypic and heterotypic signalling, which also involves microglia, neurons and oligodendrocytes. Multiple P2X and P2Y receptors are expressed by both astrocytes and microglia; however, these receptors are differentially recruited by nucleotides, depending upon specific pathophysiological conditions, and also mediate the long-term trophic changes of these cells during inflammatory gliosis. In astrocytes, P2-receptor-induced gliosis occurs via activation of the extracellular-regulated kinases (ERK) and protein kinase B/Akt pathways and involves induction of inflammatory and anti-inflammatory genes, cyclins, adhesion and antiapoptotic molecules. While astrocytic P2Y₁ and P2Y(₂,₄) are primarily involved in short-term calcium-dependent signalling, multiple P2 receptor subtypes seem to cooperate to astrocytic long-term changes. Conversely, in microglia, exposure to inflammatory and immunological stimuli results in differential functional changes of distinct P2 receptors, suggesting highly specific roles in acquisition of the activated phenotype. We believe that nucleotide-induced activation of astrocytes and microglia may originally start as a defence mechanism to protect neurons from cytotoxic and ischaemic insults; dysregulation of this process in chronic inflammatory diseases eventually results in neuronal cell damage and loss. On this basis, full elucidation of the specific roles of P2 receptors in these cells may help exploit the beneficial neuroprotective features of activated glia while attenuating their harmful properties and thus provide the basis for novel neuroprotective strategies that specifically target the purinergic system.

Figure 2

Modulation of brain inflammation by extracellular nucleotides. Traumatic and/or ischaemic events lead to the massive release of astrocytic ATP, which is rapidly degraded to ADP and maybe other nucleotides. Extracellular nucleotides activate P2Y and P2X receptors either paracrinally (1) or autocrinally (2), leading to modulation of gene expression. Several pro-inflammatory and anti-apoptotic genes have been demonstrated to be specifically upor down-regulated, which in turn results in astrocytic proliferation and growth (reactive astrogliosis). Reactive astrocytes also synthesise and release neurotrophins, pleiotrophins, cytokines, and small signalling molecules [e.g., nitric oxide (NO)], which can modulate neuronal and microglial cell survival and their reaction to noxious stimuli. Extracellular nucleotides can also directly activate ionotropic or metabotropic receptors expressed by cell types other than astrocytes (e.g., neurons and microglia), thus further contributing to the development of a first inflammatory line of defence against spreading of brain damage. Nevertheless, a chronic, sustained, and out-of-control inflammatory reaction may result in brain cell loss, and development of neurodegenerative events (see text for more details). GDNPF glial-derived neurite-promoting factor, IP-10 interferon-inducible protein 10, LIF, leukaemia inhibitory factor NT neurotrophin

Figure 1

Stimulation of glial cells from the retina evokes a radially propagating wave of elevated calcium. (a) Mechanical stimulation of a glial cell in the centre of the field of view evoked a local elevation of Ca²⁺. Subsequently, this Ca²⁺ elevation propagated to neighbouring cells. In this sequence, images were acquired at 0.93-s intervals, and the white overlay image shows the leading edge of the wavefront. (b) Putative mechanism for glial Ca²⁺ wave generation. Ca²⁺ is released from internal stores in response to elevated internal inositol-1,4,5-trisphosphate [Ins(1,4,5)P3]. Ins(1,4,5)P3 can diffuse to neighbouring cells through gap junctions to cause short-range signalling. Long-range calcium signalling requires the release of ATP, which causes the regenerative production of Ins(1,4,5)P3 and further release of ATP from neighbouring astrocytes. Reproduced with permission from [29].