Pathological Potential of Astroglial Purinergic Receptors

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.

Astroglial Ca2+-Dependent Hyperexcitability Requires P2Y1 Purinergic Receptors and Pannexin-1 Channel Activation in a Chronic Model of Epilepsy

“…It should also be noted that ATP-mediated P2Y 1 R activation is one of the key signals for the developing of reactive gliosis in several brain injury conditions (Franke and Illes, 2014 ; Shinozaki et al, 2017 ), which could explain the strong astrogliosis described previously in our epilepsy model as well as in others (Pernot et al, 2011 ; Morales et al, 2014 ; Buckmaster et al, 2017 ). Unlike previous reported findings (Di Castro et al, 2011 ), we observed that spontaneous astroglial somatic Ca 2+ signals do not require P2Y 1 R activation in the control condition, since their blockade has no effect on Ca 2+ oscillations (Figure 2 ).…”

Inflammatory Cytokines Facilitate the Sensitivity of P2X7 Receptors Toward Extracellular ATP at Neural Progenitor Cells of the Rodent Hippocampal Subgranular Zone

“…Proliferation of reactive astrocytes termed astrogliosis is mediated not only by ATP acting at P2X7Rs, but also by additional nucleotide receptors of the P2X and P2Y types [36,37]. However, ATP is only one of the numerous endogenous factors determining astrogliosis, acting alone or together with cytokines (IL, TNF, or interferons), growth factors (FGF-2 or leukemia inhibitory factor), neurotransmitters (glutamate or noradrenaline), reactive oxygen radicals, nitric oxide, etc.…”

Gliotransmission: A Novel Target for the Development of Antiseizure Drugs

“…An inflammatory process or a hypoxic or traumatic brain insult could initially activate microglia, which release ATP and stimulate neighboring astrocytes through activating purinergic receptors, including P2Y (i.e., P2Y1) and P2X (i.e., P2X7) (Franke and Illes 2014; Pascual and others 2012). Activated astrocytes consequently release more ATP through Ca 2+ -dependent exocytotic and nonexocytotic processes, with the spread of Ca 2+ waves within the astrocyte network as the amplifying mechanism (Pascual and others 2012).…”

“…The ATP released from astrocytes can enter the extracellular space, likely via connexin and pannexin hemichannels, which can be inhibited by 10PanX and GAP26 mimetic peptides (Shigetomi and others 2018; Wellmann and others 2018), and by Ca 2+ -dependent vesicular exocytosis. This pathway generates slow, long-lasting P2Y1-mediated astrocytic Ca 2+ transients that propagate on a large scale (Shigetomi and others 2018; Wellmann and others 2018), thereby inducing astrogliosis in the astrocyte network (Franke and Illes 2014; Shinozaki and others 2017). Reactive astrocytes subsequently overexpress P2Y1 receptors, which have been implicated in the generation of long-lasting astrocytic Ca 2+ transients in astrocytes (Alves and others 2017; Franke and Illes 2014; Pascual and others 2012; Shigetomi and others 2018).…”

“…Both theories have been used to explain drug-resistance in DRE with the goal of mitigating alterations in neuronal excitability (e.g., lamotrigine) or synaptic neurotransmission (e.g., levetiracetam); however, the theories do not take into consideration other cellular components of the central nervous tissue such as glial cells, which have an active role in modulating synaptic plasticity and electrical properties in the normal brain (Amiri and others 2012; Bonansco and others 2011; Fellin and others 2004; Lalo and others 2014; Panatier and others 2011; Perea and Araque 2007; Perea and others 2016; Steinhaüser and others 2016). This neurocentric view of epilepsy is changing and a growing body of evidence reveals that reactive astrocytes contribute actively in epileptogenesis and in seizure activity (Alves and others 2017; Fedele and others 2005; Franke and Illes 2014; Gomez-Gonzalo and others 2010; Wellmann and others 2018). Astrocytes undergo morphological, molecular, and functional modifications that allow astrogliosis to develop, along with changes in the expression pattern of various proteins such as transporters, hemichannels, receptors, and enzymes, some of which are an integral part of signaling between astrocyte–neuron and astrocyte–astrocyte communication (Jabs and others 2008; Steinhaüser and others 2016).…”