Review
Trophic functions of nucleotides in the central nervous system

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In addition to short-term effects, one of the fundamental roles of extracellular nucleotides in the central nervous system involves long-term trophic effects. Physiological outcomes include neurogenesis, neuronal differentiation, glial proliferation, migration, growth arrest and apoptosis. Nucleotides exert these functions via P2-receptor-mediated mechanisms that can also interact with polypeptide-growth-factor-mediated or integrin-mediated signaling pathways. In addition, pathogenic roles for extracellular nucleotides in response to central nervous system injury including trauma and ischemia have been observed after the release of nucleotides by damaged and dying cells and in the development of neuropathic and inflammatory pain. Here, we illuminate the contribution of extracellular nucleotides to the development, growth, cellular plasticity and death of neural cells and the mechanisms regulating these trophic effects.

Introduction

Long-term trophic effects represent one of the fundamental functional roles of extracellular nucleotides in the central nervous system (CNS). These include a wide range of outcomes such as neurogenesis, neuronal differentiation, glial proliferation, migration, growth arrest and apoptosis. The exceptional range of these effects reflects the wide distribution of nucleotide receptors on all cell types of the nervous system, the multiplicity of P2 receptor subtypes and subtype-specific and cell-type-specific intracellular downstream signaling pathways.

Section snippets

Nucleotide receptors and signaling pathways

As summarized elsewhere [1], nucleotides act via ionotropic or G-protein-coupled receptors (GPCRs) termed purinergic P2 receptors. The homomeric or heteromeric P2X receptors (seven subtypes, P2X1 to P2X7) are stimulated by ATP and represent Na+-, K+-, and Ca2+-permeable ion channels. Depending on the subtype, the eight P2Y receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14) are activated by ATP, ADP, UTP, UDP, NAD+ or nucleotide sugars and couple to differential intracellular

Astrocytes as targets of nucleotides and trophic factors

Among the various cell types of the CNS, astrocytes have been early on in the focus of P2 receptor signaling (Figure 2). These studies provided important insight not only into the functional impact of nucleotides but also into the molecular mechanisms of action. Trophic actions mediated via P2Y receptors in vitro and in vivo include the induction of proliferation, stellation (the generation and elongation of astrocyte processes) and migration. P2Y receptors coupled to extracellular signal

CNS injury, astrogliosis and CNS repair

Extracellular nucleotides and purinergic signaling are key players in a large variety of disorders of the CNS 5, 10. After CNS injury, astrocytes react in a hypertrophic and hyperplastic manner that contributes to the formation of the glial scar. Astrogliosis is characterized by stellation, an increase in the expression of glial fibrillary acidic protein (GFAP) and, in some types of injury, by cellular proliferation. Application of ATP or other P2 receptor agonists to cultured astrocytes or

Microglia: versatile sensors of changes in extracellular nucleotide concentrations

Microglia, the resident immune cells of the CNS, carry several types of P2Y and P2X receptors (Figure 2). The involvement of microglia in essentially every neurological disease and the in-depth insight into the role of purinergic signaling in inflammation has previously been reviewed in detail 27, 42. In this functional context, the P2X7 receptor has a central role in the ATP-induced cytokine release from activated microglia, including interleukin 1β and interleukin 10. Via P2Y12 and P2X4

Microglia, P2 receptors and pain

It had been recognized for some time that ATP via P2X3 receptors and P2X2/3 heteromeric receptors leads to activation of peripheral nociceptive neurons [52]. An exciting recent development concerns the elucidation of a role of ATP and several P2 receptors in the development of chronic pain through a central inflammatory pathway involving glial–neuronal interactions. In a model of tactile allodynia, peripheral nerve injury was found to enhance the expression of P2X4 receptors in the activated

Oligodendrocytes and Schwann cells, stimulated and endangered

Purinergic signaling exerts opposing trophic effects on oligodendrocytes and Schwann cells, the myelin-producing cells of the CNS and peripheral nervous system (PNS), respectively (Figure 2). Electrical impulse activity leads to the release of ATP from axons, and this inhibits Schwann cell proliferation and differentiation into myelin-producing cells. But for oligodendrocytes, ATP and its breakdown products ADP and adenosine stimulate migration, differentiation and myelination by a mechanism

Nucleotides impact on embryonic neurogenesis and organ development

A newly emerging field of trophic purinergic signaling in the brain concerns neural development including progenitor cell proliferation, cell migration, differentiation, neurite outgrowth and synaptic network formation. Box 2 summarizes in a nutshell important aspects of neurogenesis in the embryonic and adult mammalian CNS. The transient developmental expression of defined purinergic receptor subtypes and of ectonucleotidases, as revealed by physiological or cytological criteria, provides a

Emerging role in adult neurogenesis

Similar purinergic mechanisms seem to be involved in adult neurogenesis (Figure 2, Figure 4). Neurospheres derived from the adult mouse SVZ express P2Y1 and P2Y2 nucleotide receptors, resulting in the generation of rapid ATP-, ADP- or UTP-induced Ca2+ transients 74, 75, 76. Agonists of these receptors were found to augment cell proliferation in the presence of growth factors, inferring nucleotide-receptor-mediated and growth-factor-receptor-mediated synergism with progenitor cell proliferation.

Where does the ATP come from?

Understanding the mechanisms and regulation of nucleotide release is important for evaluating onset and extent of purinergic signaling. Spontaneous and transient local ATP release was observed in neurospheres cultured from the adult SVZ [76] and in the embryonic chick retinal pigment epithelium [70]. Hemichannels (connexin43) seem to represent an important source of ATP released from radial glial cells [71] and retinal pigment epithelial cells [70]. During mid-cortical neurogenesis,

Neuronal differentiation, cell survival and cell death: role of receptor subtypes

Nucleotide-induced neurite outgrowth and survival has been demonstrated for a variety of in vitro systems including PC12 cells and dorsal root ganglion neurons (for reviews, see Refs 26, 62, 81; Figure 2). Extracellular ATP itself does not seem to affect differentiation of PC12 cells, but NGF and P2Y2 receptor coactivation synergistically induced neurite outgrowth [81], resulting from Src family kinase-regulated molecular crosstalk between P2Y2 receptor activation and TrkA receptor tyrosine

Network formation, a field to be developed

To date, there is only scarce information concerning the role of ATP and other nucleotides in the development of synaptic network activity. In the neonatal rat hippocampus, endogenous ATP contributes to sculpt the neural circuit at early stages of postnatal development. ATP, via ionotropic P2X receptors, was found to modulate the expression of giant depolarizing potentials, which seem to play a key part in the development of the adult circuit [94]. Through P2Y1 receptors, ATP exerted an

Concluding remarks

By way of the multiplicity of P2 receptors and their potential to interact with other signaling pathways, nucleotides exert a multitude of trophic effects on neural cells. Recent studies uncovered novel mechanisms of nucleotide-mediated functional and structural plasticity in astrocytes, oligodendrocytes, Schwann cells, microglia and neurons and began to elucidate the underlying signaling cascades that are highly relevant regarding the functional role of nucleotides in both physiology and

Acknowledgements

Work was supported by the Deutsche Forschungsgemeinschaft (140/17–3 to H.Z.; www.dfg.de), the Department of Veterans Affairs (to J.T.N.; www.va.gov) and the National Institutes of Health (NS46651 to J.T.N.; www.nih.gov).

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